(Azetidin-1-ylalkyl) lactams as tachykinin antagonists

ABSTRACT

The present invention provides compounds of formula (I) and the pharmaceutically acceptable salts thereof, wherein R is C 3  -C 7  cycloalkyl, aryl or C 1  -C 6  alkyl, said C 1  -C 6  alkyl, said C 1  -C 6  alkyl being optionally substituted by fluoro, COOH, --COO(C 1  -C 4  alkyl), C 3  -C 7  cycloalkyl, adamantyl, aryl or het 1 , and said C 3  -C 7  cycloalkyl being optionally substituted by 1 or 2 substituents each independently selected from C 1  -C 4  alkyl, C 3  -C 7  cycloalkyl, C 1  -C 4  alkoxy, hydroxy, fluoro, fluoro (C 1  -C 4 ) alkyl and fluoro (C 1  -C 4 ) Alkoxy; R 1  is phenyl, naphthyl, thienyl, benzothienyl or indolyl, each optionally substituted by 1 or 2 substituents each independently selected from C 1  -C 4  alkyl, C 1  -C 4  alkoxy, halo and trifluormethyl; R 2  is --CO 2  H, --CONR 3  R 4 , --CONR 5  (C 3  -C 7  cycloalkyl), --NR 5  (C 2  -C 5  alkanoyl), --NR 3  R 4 , --NR 5  CONR 5  R 6 , (C 3  -C 7  cycloalkyl-C 1  -C 4  alkyl)R 5  N--, --NR 5  COCF 3 , --NR 5  SO 2  CF 3 , --NR 5  (SO 2  C 1  -C 4  alkyl), --NR 5  SO 2  NR 5  R 6 , --NR 5  (SO 2  aryl), --N(aryl) (SO 2  C 1  -C 4  alkyl), --OR 5 , --O(C 3  -C 7  cycloalkyl), --SO 2  NR 5  R 6 , het 3  or a group of formulas: (a), (b), (c), (d), (e), (f), (g) or (h); X is C 1  -C 4  alkylene; X 1  is a direct link or C 1  -C 6  alkylene; X 2  is a direct link, CO, SO 2 , or NR 5  CO; and m is 0, 1 or 2; together with intermediates used in the preparation of compositions containing and the use as tachykinin angatonists of such derivatives. ##STR1##

Priority is claimed under 35 U.S.C. #371 from PCT/EP95/30504 filed Jul.29, 1995.

This invention relates to lactams. More particularly, this inventionrelates to azetidinylalkyllactam derivatives and to processes for thepreparation of, intermediates used in the preparation of, compositionscontaining and uses of, such derivatives.

The present azetidinylalkyllactam derivatives are antagonists oftachykinins, including NKA, NKB and Substance P, acting at the humanneurokinin-1 (NK₁), neurokinin-2 (NK₂) or neurokinin-3 (NK₃) receptor,or a combination thereof. The derivatives are therefore useful forpreventing or treating an inflammatory disease such as arthritis,psoriasis, asthma or inflammatory bowel disease, a central nervoussystem (CNS) disorder such as anxiety, depression, dementia orpsychosis, a gastro-intestinal (GI) disorder such as functional boweldisease, irritable bowel syndrome, gastro-oesophageal reflux, faecalincontinence, colitis or Crohn's disease, an urogenital tract disordersuch as incontinence, hyperreflexia or cystitis, a pulmonary disordersuch as chronic obstructive airways disease, an allergy such as eczema,contact dermatitis or rhinitis, a hypersensitivity disorder such aspoison ivy, a vasospastic disease such as angina or Reynaud's disease, afibrosing or collagen disease such as scleroderma or eosinophillicfascioliasis, reflux sympathetic dystrophy such as shoulder/handsyndrome, an addiction disorder such as alcoholism, a stress-relatedsomatic disorder, a peripheral neuropathy such as diabetic neuropathy,neuralgia, causalgia, painful neuropathy, a burn, herpetic neuralgia orpost-herpetic neuralgia, a neuropathological disorder such asAlzheimer's disease or multiple sclerosis, a disorder related to immuneenhancement or suppression such as systemic lupus erythematosis, arheumatic disease such as fibrositis or emesis, cough, acute or chronicpain or migraine. The present derivatives are particularly potent andselective antagonists of achykinins, including NKA, NKB and Substance P,acting at the human NK₂ eceptor. They are particularly useful fortreating or preventing an inflammatory isease such as arthritis,psoriasis, asthma or inflammatory bowel disease, a entral nervous system(CNS) disorder such as anxiety, depression, dementia or psychosis, agastrointestinal (GI) disorder such as functional bowel disease,irritable bowel syndrome, gastro-oesophageal reflux, faecalincontinence, colitis or Crohn's disease, an urogenital tract disordersuch as incontinence or cystitis, a pulmonary disorder such as chronicobstructive airways disease, an allergy such as eczema, contactdermatitis or rhinitis, a hypersensitivity disorder such as poison ivy,a peripheral neuropathy such as diabetic neuropathy, neuralgia,causalgia, painful neuropathy, a burn, herpetic neuralgia orpost-herpetic neuralgia, cough or acute or chronic pain.

The present invention provides compounds of the formula: ##STR2## andthe pharmaceutically acceptable salts thereof, wherein R is C₃ -C₇cycloalkyl, aryl or C₁ -C₆ alkyl, said C₁ -C₆ alkyl being optionallysubstituted by fluoro, --COOH, --COO(C₁ -C₄ alkyl), C₃ -C₇ cycloalkyl,adamantyl, aryl or het¹, and said C₃ -C₇ cycloalkyl being optionallysubstituted by 1 or 2 substituents each independently selected from C₁-C₄ alkyl, C₃ -C₇ cycloalkyl, C₁ -C₄ alkoxy, hydroxy, fluoro, fluoro(C₁-C₄)alkyl and fluoro(C₁ -C₄)alkoxy;

R¹ is phenyl, naphthyl, thienyl, benzothienyl or indolyl, eachoptionally substituted by 1 or 2 substituents each independentlyselected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo and trifluoromethyl;

R² is --CO₂ H, --CONR³ R⁴, --CONR⁵ (C₃ -C₇ cycloalkyl), --NR (C₂ -C₅alkanoyl), --NR³ R⁴, --NR⁵ CONR⁵ R⁶, (C₃ -C₇ cycloalkyl-C₁ -C₄ alkyl)R⁵N--, (C₃ -C₇ cycloalkyl-C₁ -C₄ alkyl)₂ N--, --NR⁵ COCF₃, --NR⁵ SO₂ CF₃,--NR⁵ (SO₂ C₁ -C₄ alkyl), --NR⁵ SO₂ NR⁵ R⁶, --NR⁵ (SO₂ aryl),--N(aryl)(SO₂ C₁ -C₄ alkyl), --OR⁵, --O(C₃ -C₇ cycloalkyl), --SO₂ NR⁵R⁶, het³ or a group of the formula: ##STR3## R³ and R⁴ are eachindependently selected from H and C₁ -C₄ alkyl optionally substituted byhydroxy, C₁ -C₄ alkoxy, --S(O)_(p) (C₁ -C₄ alkyl), amino, --NH(C₁ -C₄alkyl), --N(C₁ -C₄ alkyl)2 or het² ;

R⁵ and R⁶ are each independently selected from H, C₁ -C₄ alkyl and C₃-C₇ cycloalkyl-C₁ -C₄ alkyl, said C₁ -C₄ alkyl and C₃ -C₇ cycloalkyl-C₁-C₄ alkyl being optionally substituted by fluoro;

R⁷ is H, C₁ -C₄ alkyl, hydroxy, fluoro(C₁ -C₄)alkyl or phenyl, saidphenyl being optionally substituted by 1 or 2 substituents eachindependently selected from C₁ -C₄ alkyl, fluoro(C₁ -C₄)alkyl, halo, C₁-C₄ alkoxy and fluoro(C₁ -C₄)alkoxy;

R⁸ is H, fluoro, hydroxy, C₁ -C₄ alkoxy, C₂ -C₅ alkanoyl or C₂ -C₅alkanoyloxy;

R⁹ is --NR⁵ R⁶, --NR⁵ COR⁵, --NR⁵ SO₂ CF₃, --NR⁵ (SO₂ C₁ -C₄ alkyl),--NR⁵ SO₂ NR⁵ R⁶, --NR⁵ COO(C₁ -C₄ alkyl), --NR⁵ CONR⁵ R⁶, --NR⁵ (SO₂morpholino), --NR⁵ (SO₂ aryl), --N(aryl)(SO₂ C₁ -C₄ alkyl) or a group ofthe formula: ##STR4## X is C₁ -C₄ alkylene; X¹ is a direct link or C₁-C₆ alkylene;

X² is a direct link, CO, SO₂ or NR⁵ CO;

W is methylene, CO, CH(OH), C(OH)₂, CH(C₁ -C₄ alkoxy), CHCO₂ H, CHCO₂(C₁ -C₄ alkyl), CHCONR⁵ R⁶, CHF, CF₂, CH(azetidin-1-yl),CH(pyrrolidin-1-yl), CH(piperidin-1-yl), CH(morpholino),CH(benzoxazol-2-yl), CHR⁹, O, S(O)_(p), NR⁵, N(C₃ -C₇ cycloalkyl), NSO₂(C₁ -C₄ alkyl), NSO₂ NR⁵ R⁶, NSO₂ CF₃, NSO₂ (morpholino), NSO₂ (aryl),##STR5## NCONR⁵ R⁶, NCOR⁵, NCO(aryl) or NCO₂ (C₁ -C₄ alkyl);

W¹ is methylene, CO, CH(OH), C(OH)₂, CH(C₁ -C₄ alkoxy), CHCO₂ H, CHCO₂(C₁ -C₄ alkyl), CHCONR⁵ R⁶, CHF, CF₂, CH(azetidin-1-yl),CH(pyrrolidin-1-yl), CH(piperidin-1-yl), CH(morpholino) or CHR⁹ ;

W² is W¹, --CH₂ W¹ --, --CH₂ WCH₂ -- or --CH₂ CH₂ WCH₂ --;

m is 0, 1 or 2;

n is 1 or 2 when W is other than methylene and is 0, 1 or 2 when W ismethylene;

p is 0, 1 or 2;

q is 1 or 2;

r is 1, 2, 3 or 4;

"aryl", used in the definition of R, R², R⁹ and W, means naphthyl orphenyl, each optionally substituted by C₁ -C₄ alkyl, halo, --OR⁵,fluoro(C₁ -C₄)alkyl, C₂ -C₅ alkanoyl, --CONR⁵ R⁶, --SO₂ NR⁵ R⁶ orphenyl;

"het¹ ", used in the definition of R, means thienyl or a 5- or6-membered ring heteroaryl group containing either 1 or 2 nitrogenheteroatoms, or one nitrogen heteroatom and one oxygen or sulphurheteroatom, each optionally substituted by 1 or 2 substituents eachindependently selected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, fluoro(C₁-C₄)alkyl and fluoro(C₁ -C₄)alkoxy;

"het² ", used in the definitions of R³ and R⁴, means a 4- to 7-memberedring, non-aromatic, heterocyclic group containing 1 or 2 heteroatomseach independently selected from nitrogen, oxygen and S(O)_(p), saidgroup being optionally C-substituted by 1 or 2 substituents eachindependently selected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy and fluoro(C₁-C₄)alkyl, and said ring nitrogen heteroatom optionally bearing a H, C₁-C₄ alkyl, C₂ -C₅ alkanoyl, --CONR⁵ R⁶ or --SO₂ NR⁵ R⁶ substituent;

and "het³ ", used in the definition of R², means an optionallybenzo-fused, N-linked, 5-membered ring heteroaryl group containing from1 to 4 nitrogen heteroatoms, optionally substituted, including in thebenzo-fused portion, by 1 or 2 substituents each independently selectedfrom C₁ -C₄ alkyl, fluoro and fluoro(C₁ -C₄)alkyl.

In the above definitions, the term "halo" means fluoro, chloro, bromo oriodo and alkyl, alkylene and alkoxy groups containing three or morecarbon atoms and alkanoyl groups containing four or more carbon atomscan be straight- or branched-chain.

Preferably, R is C₁ -C₆ alkyl optionally substituted by --COOH, --COO(C₁-C₄ alkyl), C₃ -C₇ cycloalkyl, aryl or het¹, said cycloalkyl beingoptionally substituted by 1 or 2 substituents each independentlyselected from C₁ -C₄ alkyl and fluoro.

More preferably, R is C₁ -C₆ alkyl optionally substituted by --COOH,--COO(C₁ -C₄ alkyl), C₃ -C₇ cycloalkyl optionally substituted by 1 or 2substituents each independently selected from C₁ -C₄ alkyl and fluoro,phenyl optionally substituted by 1 or 2 substituents each independentlyselected from C₁ -C₄ alkyl, halo, C₁ -C₄ alkoxy, fluoro(C₁ -C₄)alkyl, C₂-C₅ alkanoyl, --SO₂ N(C₁ -C₄ alkyl)₂ and phenyl, or a 5- or 6-memberedring heteroaryl group containing 1 or 2 nitrogen heteroatoms.

Yet more preferably, R is C₁ -C₆ alkyl optionally substituted by --COOH,--COO(C₁ -C₄ alkyl), C₃ -C₇ cycloalkyl optionally substituted by 1 or 2substituents each independently selected from methyl and fluoro, phenyloptionally substituted by 1 or 2 substituents each independentlyselected from methyl, fluoro, chloro, methoxy, trifluoromethyl, acetyl,--SO₂ N(CH₃)₂ and phenyl, or pyridinyl.

Yet further preferably, R is 5-carboxypentyl,5-tert-butyloxycarbonylpentyl, cyclopropylmethyl, dicyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl,2-methylcyclohexylmethyl, 4,4-difluorocyclohexylmethyl,2-cyclopropylethyl, 2,2-dicyclopropylethyl, 1-cyclohexylethyl,2-cyclohexylethyl, cycloheptylmethyl, benzyl, 2-methylbenzyl,3-methylbenzyl, 4-methylbenzyl, 4-fluorobenzyl, 2,4-dichlorobenzyl,3-methoxybenzyl, 2-trifluoromethylbenzyl, 3,5-di(trifluoromethyl)benzyl,3-acetylbenzyl, 3-(N,N-dimethylsulphamoyl)benzyl, 4-phenylbenzyl,1-phenylethyl, 2-pyridinylmethyl, 3-pyridinylmethyl or4-pyridinylmethyl.

Most preferably, R is cyclopropylmethyl, dicyclopropylmethyl,2-cyclopropylethyl, 2,2-dicyclopropylethyl, cyclohexylmethyl,4,4-difluorocyclohexylmethyl, cycloheptylmethyl or benzyl.

Preferably, R¹ is phenyl optionally substituted by 1 or 2 halosubstituents.

More preferably, R¹ is phenyl optionally substituted by 1 or 2substituents each independently selected from fluoro and chloro.

Yet more preferably, R¹ is phenyl, 3,4-difluorophenyl, 3-chlorophenyl,4-chlorophenyl or 3,4-dichlorophenyl.

Most preferably, R¹ is 3,4-difluorophenyl, 4-chlorophenyl or3,4-dichlorophenyl.

Preferably, R² is --CONR³ R⁴, --CONR⁵ (C₃ -C₇ cycloalkyl), --NR³ R⁴,het³ or a group of the formula: ##STR6## where R³ and R⁴ are eachindependently selected from C₁ -C₄ alkyl and C₁ -C₄ alkyl substituted byhydroxy or C₁ -C₄ alkoxy, R⁵ and R⁶ are each independently selected fromH, C₁ -C₄ alkyl optionally substituted by fluoro and C₃ -C₇cycloalkyl-C₁ -C₄ alkyl, R⁷ is H, hydroxy or phenyl, R⁸ is hydroxy or C₂-C₅ alkanoyloxy, W is methylene, CH(OH), CH(C₁ -C₄ alkoxy), CHCO₂ H,CHCO₂ (C₁ -C₄ alkyl), CH(benzoxazol-2-yl), CHNR⁵ R⁶, CHNR⁵ COR⁵, CHNR⁵(SO₂ C₁ -C₄ alkyl), CHNR⁵ COO(C₁ -C₄ alkyl), O, S(O)_(p), NR⁵, NSO₂ (C₁-C₄ alkyl), NSO₂ NR⁵ R⁶, NSO₂ (morpholino), NCONR⁵ R⁶, NCOR⁵, NCO(aryl)or NC₂ (C₁ -C₄ alkyl), n is 1 or 2 when W is other than methylene and is0 or 1 when W is methylene, and p is 0,1 or 2.

More preferably, R² is --CONR³ R⁴, --CONR⁵ (C₃ -C₇ cycloalkyl), --NR³R⁴, a N-linked, 5-membered ring heteroaryl group containing 1 or 2nitrogen heteroatoms, or a group of the formula: ##STR7## where R³ andR⁴ are each independently selected from methyl and C₁ -C₄ alkylsubstituted by hydroxy or methoxy, R⁵ and R⁶ are each independentlyselected from H, methyl, trifluoromethyl and cyclopropylmethyl, R⁷ is H,hydroxy or phenyl, R⁸ is hydroxy or acetyloxy, W is methylene, CH(OH),CHOCH₃, CHOCH₂ CH₃, CHO(CH₂)₂ CH₃, CHOC(CH₃)₃, CHCO₂ H, CHCO₂ CH₃, CHCO₂CH₂ CH₃, CH (benzoxazol-2-yl), CHNH₂, CHNHCH₂ (cyclopropyl), CHNHCOCH₃,CHNHSO₂ CH₃, CHNHCO₂ C(CH₃)₃, O, S(O)_(p), NH, NCH₃, NCH₂ (cyclopropyl),NSO₂ CH₃, NSO₂ NH₂, NSO₂ NHCH₃, NSO₂ N(CH₃)₂, NSO₂ (morpholino), NCONH₂,NCONHCH₃, NCOCH₃, NCOCF₃, NCO(phenyl) or NCO₂ C(CH₃)₃, n is 1 or 2 whenW is other than methylene and is 0 or 1 when W is methylene, and p is 0,1 or 2.

Yet more preferably, R² is N-(2-methoxyethyl)-N-methylcarbamoyl,N-cyclohexylcarbamoyl, N-(2-hydroxyethyl)-N-methylamino,N-(2-hydroxy-2-methylpropyl)-N-methylamino,N-(2-methoxyethyl)-N-methylamino, imidazol-1-yl,3-hydroxypyrrolidin-1-yl, piperidin-1-yl, 2,6-dimethylpiperidin-1-yl,3-hydroxypiperidin-1-yl, 4-hydroxypiperidin-1-yl,4-methoxypiperidin-1-yl, 4-ethoxypiperidin-1-yl,4-(n-propoxy)piperidin-1-yl, 4-(t-butoxy)piperidin-1-yl,4-carboxypiperidin-1-yl, 4-methoxycarbonylpiperidin-1-yl,4-ethoxycarbonylpiperidin-1-yl, 4-(benzoxazol-2-yl)piperidin-1-yl,4-aminopiperidin-1-yl, 4-cyclopropyl-methylaminopiperidin-1-yl,4-acetamidopiperidin-1-yl, 4-methanesulphonamido-piperidin-1-yl,4-(t-butoxycarbonylamino)piperidin-1-yl, morpholino, 2-phenylmorpholino,homomorpholino, thiomorpholino, 1-oxothiomorpholino,1,1-dioxothiomorpholino, piperazin-1-yl, 4-methylpiperazin-1-yl,4-cyclopropylmethyl-piperazin-1-yl, 4-methanesulphonylpiperazin-1-yl,4-aminosulphonylpiperazin-1-yl, 4-methylaminosulphonylpiperazin-1-yl,4-dimethylaminosulphonylpiperazin-1-yl,4-morpholinosulphonylpiperazin-1-yl, 4-carbamoylpiperazin-1-yl,4-N-methylcarbamoylpiperazin-1-yl, 4-acetylpiperazin-1-yl,4-trifluoroacetylpiperazin-1-yl, 4-benzoylpiperazin-1-yl,4-(t-butoxycarbonyl)piperazin-1-yl, pyrrolidin-1-ylcarbonyl,piperidin-1-ylcarbonyl, 3-oxomorpholino, 3-hydroxy-8-azabicyclo[3,2, 1]oct-8-yl or 3-acetyloxy-8-azabicyclo[3,2, 1 ]oct-8-yl.

Most preferably, R² is 4-aminopiperidin-1-yl, 4-carboxypiperidin-1-yl,4-hydroxypiperidin-1-yl, morpholino, 1-oxothiomorpholino,4-aminosulphonylpiperazin-1-yl, 4-methanesulphonylpiperazin-1-yl,4-methylaminosulphonylpiperazin-1-yl or4-morpholinosulphonylpiperazin-1-yl.

Further preferred examples of R² include 4-fluoropiperidin-1-yl,4,4-difluoropiperidin-1-yl, 4-oxopiperidin-1-yl,4-(pentafluorophenylsulphonyl) -piperazin-1-yl and4-(4-fluorophenylsulphonyl)piperazin-1-yl.

Preferably, X is ethylene or propylene.

Most preferably, X is ethylene.

Preferably, X¹ is a direct link.

Preferably, X² is a direct link or CO.

Most preferably, X² is a direct link.

Preferably, m is 1.

The pharmaceutically acceptable salts of the compounds of the formula(I) include the acid addition and the base salts thereof.

Suitable acid addition salts are formed from acids which form non-toxicsalts and examples are the hydrochloride, hydrobromide, hydroiodide,sulphate, hydrogen sulphate, nitrate, phosphate, hydrogen phosphate,acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate,succinate, benzoate, methanesulphonate, benzenesulphonate andp-toluenesulphonate salts.

Suitable base salts are formed from bases which form non-toxic salts andexamples are the aluminium, calcium, lithium, magnesium, potassium,sodium, zinc and diethanolamine salts.

For a review on suitable salts see Berge et al, J. Pharm. Sci., 66, 1-19(1977).

A compound of the formula (I) may contain one or more asymmetric carbonatoms and may therefore exist in two or more stereoisomeric forms. Thepresent invention includes the individual stereoisomers of the compoundsof the formula (I) and mixtures thereof.

Separation of diastereoisomers may be achieved by conventionaltechniques, e.g. by fractional crystallisation, chromatography orH.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) ora suitable salt or derivative thereof. An individual enantiomer of acompound of the formula (I) may also be prepared from a correspondingoptically pure intermediate or by resolution, such as by H.P.L.C. of thecorresponding racemate using a suitable chiral support or by fractionalcrystallisation of the diastereoisomeric salts formed by reaction of thecorresponding racemate with a suitable optically active acid or base.

The preferred compounds of the formula (I) and salts thereof where X is--CH₂ CH₂ -- have the (S)-stereochemistry at the position of attachmentof the X and R¹ groups to the lactam ring.

Preferred examples of a compound of the formula (I) are those wherein:

(i) R is cyclopropylmethyl, R¹ is 3,4-dichlorophenyl, R² is morpholino,X is --CH₂ CH₂ --, X¹ is a direct link and m is 1;

(ii) R is 4,4-difluorocyclohexylmethyl, R¹ is 3,4-dichlorophenyl, R² ismorpholino, X is --CH₂ CH₂ --, X¹ is a direct link and m is 1;

(iii) R is 4,4-difluorocyclohexylmethyl, R¹ is 3,4-dichlorophenyl, R² is4-aminopiperidin-1-yl, X is --CH₂ CH₂ --, X¹ is a direct link and m is1;

(iv) R is cyclopropylmethyl, R¹ is 3,4-dichlorophenyl, R² is4-aminosulphonylpiperazin-1-yl, X is --CH₂ CH₂ --, X¹ is a direct linkand m is 1;

(v) R is 4,4-difluorocyclohexylmethyl, R¹ is 3,4-dichlorophenyl, R² is4-hydroxypiperidin-1-yl, X is --CH₂ CH₂ --, X¹ is a direct link and m is1;

(vi) R is 2-cyclopropylethyl, R¹ is 3,4-dichlorophenyl, R² ismorpholino, X is --CH₂ CH₂ --, X¹ is a direct link and m is 1;

(vii) R is 2-cyclopropylethyl, R¹ is 3,4-dichlorophenyl, R² is4-methanesulphonylpiperazin-1-yl, X is --CH₂ CH₂ --, X¹ is a direct linkand m is 1;

(viii) R is cyclopropylmethyl, R¹ is 3,4-dichlorophenyl, R² is4-fluoropiperidin-1-yl, X is --CH₂ CH₂ --, X¹ is a direct link and m is1;

(ix) R is 4,4-difluorocyclohexylmethyl, R¹ is 3,4-dichlorophenyl, R² is4-oxopiperidin-1-yl, X is --CH₂ CH₂ --, X¹ is a direct link and m is 1;

(x) R is cyclopropylmethyl, R¹ is 3,4-dichlorophenyl, R² is4-carboxypiperidin-1-yl, X is --CH₂ CH₂ --, X¹ is a direct link and m is1; or

(xi) R is cyclohexylmethyl, R¹ is 3,4-dichlorophenyl, R² is4-carboxypiperidin-1-yl, X is --CH₂ CH₂ --, X¹ is a direct link and m is1:

or any such compound with the (S)-stereochemistry at the position ofattachment of the X and R¹ groups to the lactam ring, or apharmaceutically acceptable salt of any thereof.

The compounds of the formula (I) provided by the invention can beprepared by the following methods:

1) The compounds of the formula (I) where X is (C₀ -C₃ alkylene)CH₂ --,the methylene group of which is attached to the azetidine nitrogen atom,and R, R¹, R², X¹ and m are as previously defined for a compound of theformula (I) can be prepared by reductive amination using as startingmaterials a compound of the formula: ##STR8## where R, R¹ and m are aspreviously defined for a compound of the formula (I), and a compound ofthe formula: ##STR9## , or an acid addition salt thereof, where R² andX¹ are as previously defined for a compound of the formula (I). Thereaction is preferably carried out in the presence of a suitable acid,e.g. acetic acid.

The reaction proceeds via the initial formation of an intermediateiminium salt of the formula: ##STR10## which may stable and isolatable.The reaction is preferably carried out without isolation of theintermediate of the formula (IIIA) in which case it is reduced in situto provide a compound of formula (I).

In a typical procedure, an aldehyde of the formula (II) is first reactedwith an azetidine of the formula (III) in a suitable solvent, e.g.tetrahydrofuran, and the mixture then treated with a suitable reducingagent, e.g. sodium triacetoxyborohydride or sodium cyanoborohydride, inthe presence of a suitable acid, e.g. acetic acid, to give the requiredproduct. If an acid addition salt of an azetidine of the formula (III)is used as a starting material, a suitable acid acceptor, e.g.triethylamine, can be added prior to the addition of the reducing agent.

The reaction is typically carried out at room temperature.

The starting aldehydes of the formula (II) can be prepared by the methodshown in the Scheme I: ##STR11## where R, R¹ and m are as previouslydefined for a compound of the formula (I) and Z, Z¹ and Z² are each asuitable leaving group, e.g. chloro, bromo, iodo, methanesulphonyloxy,p-toluenesulphonyloxy or trifluoromethylsulphonyloxy.

In a typical procedure, an arylmethyinitrile of the formula (IV) isfirst deprotonated using a suitable base, e.g. sodium hydride, and thenalkylated in situ with an alkylating agent of the formula (V) where Z ispreferably bromo. The reaction is typically carried out in a suitablesolvent, e.g. tetrahydrofuran, at about 0° C. for the deprotonation andat about room temperature for the alkylation. The reaction can also becarried out under phase transfer conditions using a suitable base, e.g.sodium hydroxide, a suitable phase transfer catalyst, e.g.tetra-n-butylammonium chloride, and a suitable solvent, e.g.cyclohexane, n-pentane or toluene.

The acetonitrile derivative of the formula (VI) that is produced is thenfirst deprotonated using a suitable base, e.g. lithium diisopropylamide,and then alkylated in situ with a compound of the formula (VII) where Z¹is preferably bromo. The reaction is typically carried out in a suitablesolvent, e.g. tetrahydrofuran, at about -70° C., warming to about roomtemperature to complete the reaction. Tetra-n-butylammonium iodide canoptionally be added following addition of the compound of the formula(VII) to increase the rate of reaction.

The compound of the formula (VIII) prepared is then reduced and cyclisedto a lactam of the formula (IX) under suitable conditions, e.g. usingRaney nickel under an atmosphere of hydrogen at atmospheric pressure androom temperature using ammoniacal ethanol as the solvent.

The lactam of the formula (IX) is then first deprotonated using asuitable base, e.g. sodium hydride, and then alkylated in situ with acompound of the formula RZ² where Z² is preferably bromo,methanesulphonyloxy or p-toluenesulphonyloxy. The reaction is typicallycarried out in a suitable solvent, e.g. dimethylformamide, and at aboutroom temperature.

The lactam of the formula (X) produced is then treated with a saturatedsolution of hydrogen chloride in a suitable C₁ -C₄ alcohol, e.g.methanol, at about room temperature to remove the tetrahydropyranprotecting group. The deprotection can also be carried out using asuitable ion exchange resin, e.g. Amberlyst 15 (trade mark), and in asuitable solvent, e.g. methanol.

The alcohol of the formula (XI) prepared is oxidised to an aldehyde ofthe formula (II) under suitable conditions, e.g. under Swern oxidationconditions (oxalyl chloride, dimethylsulphoxide, triethylamine, andusing dichloromethane as the solvent).

The starting azetidines of the formula (III) may be prepared byconventional methods.

2) The compounds of the formula (I) where X, X¹, R, R¹, R² and m are aspreviously defined for a compound of the formula (I) except thosecompounds where R is trifluoromethyl, --CF₂ (C₁ -C₅ alkyl optionallysubstituted by fluoro) or aryl, can be prepared by alkylation of aN-deprotonated form of a compound of the formula: ##STR12## where X, X¹,R¹, R² and m are as previously defined for a compound of the formula(I), with a compound of the formula:

    RZ.sup.2

where R is as previously defined for this method and Z² is a suitableleaving group, e.g. chloro, bromo, iodo, methanesulphonyloxyp-toluenesulphonyloxy or trifluoromethylsulphonyloxy.

In a typical procedure, a compound of the formula (XII) is firstdeprotonated with a suitable base, e.g. sodium hydride, and thenalkylated in situ with a compound of the formula RZ² where Z² ispreferably chloro, bromo or methanesulphonyloxy. The reaction istypically carried out in a suitable solvent, e.g. dimethylformamide, atfrom room temperature to 50° C.

Alternatively, the reaction can be carried out by reacting the startingmaterials of the formulae (XII) and RZ² together in the presence of asuitable base, e.g. potassium hydroxide, and in a suitable solvent, e.g.dimethylsulphoxide, at about room temperature. If a compound of theformula RZ² where Z² is chloro is used, potassium iodide may also beadded to increase the rate of reaction.

The starting materials of the formula (XII) can be prepared byconventional methods such as by adaptation of the preparation describedin Method (1) and Scheme I (i.e. by omission of the N-alkylation step toform compounds of the formula (X)).

The starting compounds of the formula RZ² can be prepared byconventional methods.

3) All the compounds of the formula (I) where X, X¹, R, R¹, R² and m areas previously defined for a compound of the formula (I) can be preparedby reaction of a compound of the formula: ##STR13## where X, R, R¹ and mare as previously defined for a compound of the formula (I) and Z³ is asuitable leaving group, e.g. chloro, bromo, iodo, methanesulphonyloxy,trifluoromethanesulphonyloxy or p-toluenesulphonyloxy, with a compoundof the formula: ##STR14## where R² is as previously defined for acompound of the formula (I).

In a typical procedure, a compound of the formula (XIII), where Z³ ispreferably methanesulphonyloxy, is reacted with a compound of theformula (III) in the presence of a suitable acid acceptor, e.g.triethylamine or potassium carbonate or a combination thereof, in asuitable solvent, e.g. acetonitrile, and at about the reflux temperaturethereof. The compound of the formula (III) can be prepared in situ froman acid addition salt thereof by using a molar excess of the acidacceptor. The starting materials of the formula (XIII) may be preparedby conventional methods such as by hydroxy functional grouptransformation of alcohols of the formula (XI), e.g. where Z³ ismethanesulphonyloxy, by reaction of an alcohol of the formula (XI) withmethanesulphonyl chloride in the presence of a suitable acid acceptorsuch as triethylamine.

4) The compounds of the formula (I) where R¹ is phenyl and X, X¹, R, R²and m are as previously defined for a compound of the formula (I) can beprepared by hydrogenolysis of a compound of the formula (I) where R¹ isphenyl substituted by chloro, bromo or iodo and X, X¹, R, R² and m areas previously defined for a compound of the formula (I).

In a typical procedure the hydrogenolysis is carried out in ammoniacalethanol using a suitable catalyst, e.g. Raney nickel or, preferably,palladium-on-carbon, at about 50° C. and under an atmosphere of hydrogenat about 345 kPa (50 psi).

5) The compounds of the formula (I) where R² is a group of the formula:

    --NHR.sup.4, (C.sub.3 -C.sub.7 cycloalkyl-C.sub.1 -C.sub.4 alkyl)HN--, ##STR15## R.sup.9 is --NHR.sup.5, W is NH or CHNHR.sup.5, W.sup.1 is CHNHR.sup.5, W.sup.2 is W.sup.1, --H.sub.2 W.sup.1 --, --CH.sub.2 WCH.sub.2 -- or --CH.sub.2 CH.sub.2 WCH.sub.2 --, and X, X.sup.1, X.sup.2, R, R.sup.1, R.sup.5, R.sup.6, R.sup.7, m and n are as previously defined for a compound of the formula (I), can be prepared by deprotection of a compound of the formula: ##STR16## where R.sup.10 is a group of the formula:

    --NZR.sup.4 R.sup.4, (C.sub.3 -C.sub.7 cycloalkyl-C.sub.1 -C.sub.4 alkyl)Z.sup.4 N--, ##STR17## , respectively, R.sup.9A is --NZ.sup.4 R.sup.5, W.sup.A is NZ.sup.4 or CHNZ.sup.4 R.sup.5, W.sup.1A is CHNZ.sup.4 R.sup.5, W.sup.2A is W.sup.1A, --CH.sub.2 W.sup.1A --, --CH.sub.2 W.sup.A CH.sub.2 -- or --CH.sub.2 CH.sub.2 W.sup.A CH.sub.2 --, X, X.sup.1, X.sup.2, R, R.sup.1, R.sup.4, R.sup.5, R.sup.6, R.sup.7, m and n are as previously defined for a compound of the formula (I) and Z.sup.4 is a suitable protecting group, e.g. t-butoxycarbonyl (e.g. a compound of the formula (I) where W is NCO.sub.2 C(CH.sub.3).sub.3 or R.sup.9 is --NR.sup.5 CO.sub.2 C(CH.sub.3).sub.3) or benzyloxycarbonyl.

Suitable protecting groups that may be used in this Method, togetherwith methods for deprotection, are well known to the skilled person,e.g. see Greene et al, "Protective Groups in Organic Synthesis", SecondEdition, 1991, Wiley-Interscience.

In a typical procedure where Z⁴ is t-butoxycarbonyl, the deprotectioncan be carried out using trifluoroacetic acid in a suitable solvent,e.g. dichloromethane, at room temperature.

The starting materials of the formula (XIV) can be prepared byconventional methods such as by appropriate adaptation of the Methodsdescribed herein for preparing the compounds of the formula (I).

6) The compounds of the formula (I) where R² is a group of the formula:##STR18## where p is 1 or 2, W² is --CH₂ S(O)_(p) CH₂ -- or --CH₂ CH₂S(O)_(p) CH₂ -- and X, X¹, X², R, R¹, R⁵, R⁶, R⁷, m and n are aspreviously defined for a compound of the formula (I) can be prepared byoxidation of a compound of the formula (I) where R² is a group of theformula: ##STR19## , as appropriate, wherein W² is --CH₂ (S or SO)CH₂ --or --CH₂ CH₂ (S or SO)CH₂ --, and X, X¹, X², R, R¹, R⁵, R⁶, R⁷, m and nare as previously defined for a compound of the formula (I). Theoxidation is carried out with at least one molar equivalent of asuitable oxidising agent when converting a sulphoxide to a sulphone, atleast two molar equivalents of a suitable oxidising agent whenconverting a sulphide to a sulphone and substantially one molarequivalent of a suitable oxidising agent for the conversion of asulphide to a sulphoxide.

Suitable oxidising agents and conditions for this purpose are aqueoushydrogen peroxide solution under basic conditions (e.g. in the presenceof potassium carbonate, acetonitrile and using methanol as the solvent)or m-chloroperbenzoic acid in a suitable solvent, e.g. dichloromethane.

7) The compounds of the formula (I) where R² is a group of the formula:##STR20## and X, X¹, R, R¹ and mare as previously defined for a compoundof the formula (I), can be prepared by deprotection of a compound of theformula: ##STR21## where Z⁵ is a suitable protecting group, e.g. acetyl(i.e. a compound of the formula (I) where R⁸ is acetyloxy) ortetrahydropyran-2-yl, and X, X¹, R, R¹ and m are as previously definedfor a compound of the formula (I).

Suitable protecting groups that may be used for this Method, togetherwith methods for deprotection, are well known to the skilled person,e.g. see Greene et al, "Protective Groups in Organic Synthesis", SecondEdition, 1991, Wiley-Interscience.

In a typical procedure where Z⁵ is acetyl the deprotection can becarried out using an aqueous alcoholic solution of a suitable strongbase, e.g. sodium hydroxide. The reaction is typically carried out inaqueous methanol at about room temperature.

The starting materials of the formula (XV) can be prepared byconventional methods such as by adaptation of the Methods describedherein for preparing the compounds of the formula (I).

8) The compounds of the formula (I) where X, X¹, R, R¹, R² and m are aspreviously defined for a compound of the formula (I) except those whereR² is --CO₂ H, R is C₁ -C₆ alkyl substituted by --COOH, W is CHCO₂ H orW¹ is CHCO₂ H, can be prepared by intramolecular dehydration of acompound of the formula: ##STR22## where X, X¹, R, R¹, R² and m are aspreviously defined for this Method.

In a typical procedure, the dehydration is carried out under Dean-Starkconditions in a suitable solvent, e.g. toluene, and in the presence of asuitable acid, e.g. p-toluenesulphonic acid. Alternatively, thedehydration can be carried out by stirring a solution of a compound ofthe formula (XVI) in a suitable solvent, e.g. dichloromethane, in thepresence of silica gel.

The starting materials of the formula (XVI) can be prepared byconventional methods.

9) The compounds of the formula (I) where X, X¹, R, R¹, R² and m are aspreviously defined for a compound of the formula (I) except those whereR² is --CO₂ H, R is C₁ -C₆ alkyl substituted by --COOH, W is CHCO₂ H orW¹ is CHCO₂ H, can be prepared by cyclisation of a compound of theformula: ##STR23## where X, X¹, R, R¹, R² and m are as previouslydefined for this Method and Z⁶ is a suitable leaving group, e.g. C₁ -C₄alkoxy, benzyloxy, imidazol-1-yl or benzotriazol-1-yloxy.

In typical procedures:

(i) where Z⁶ is C₁ -C₄ alkoxy or benzyloxy, a solution of a compound ofthe formula (XVII) in a suitable solvent, e.g. methanol or ethanol, isheated at about the reflux temperature of the solvent;

(ii) where Z⁶ is imidazol-1-yl, a compound of the formula (XVII) isderived by reacting a compound of the formula (XVI) with1,1'-carbonyl-diimidazole in a suitable solvent, e.g. dichloromethane,and in situ cyclisation of the intermediate imidazolide provides therequired product; and

(iii) where Z⁶ is benzotriazol-1-yloxy, a compound of the formula (XVII)is derived in situ by reacting a compound of the formula (XVI) with1-hydroxybenzotriazole in the presence of a suitable dehydrating agent,e.g. 1,3-dicyclohexylcarbodiimide, and in a suitable solvent, e.g.dichloromethane, and in situ cyclisation provides the required product.

The starting materials of the formula (XVII) can be prepared byconventional methods such as from a compound of the formula (XVI),examples of which are described above.

10) The compounds of the formula (I) where X¹ is a direct link and R² is--NR³ R⁴, (C₃ -C₇ cycloalkyl-C₁ -C₄ alkyl)R⁵ N--, (C₃ -C₇ cycloalkyl-C₁-C₄ alkyl)₂ N--, or is a group of the formula: ##STR24## and X, W, W¹,R, R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, m and n are as previously defined fora compound of the formula (I), can be prepared by reaction of a compoundof the formula: ##STR25## where X, R, R¹ and m are as previously definedfor a compound of the formula (I) and Z⁷ is a suitable leaving group,e.g. methanesulphonyloxy or p-toluene sulphonyloxy, with a compound ofthe formula:

    HNR.sup.3 R.sup.4, (C.sub.3 -C.sub.7 cycloalkyl-C.sub.1 -C.sub.4 alkyl)R.sup.5 NH, (C.sub.3 -C.sub.7 cycloalkyl-C.sub.1 -C.sub.4 alkyl).sub.2 NH, ##STR26## ,respectively, where W, W.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9 and n are as previously defined for a compound of the formula (I).

In a typical procedure, the reaction is carried out using an excess ofthe amine and in a suitable solvent, e.g. acetonitrile ordichloromethane, and at the reflux temperature of the solvent.Alternatively, a further suitable acid acceptor, e.g. potassiumcarbonate, can be added to the reaction mixture.

The starting amines can be prepared by conventional methods.

The starting materials of the formula (XVIII) can also be prepared byconventional methods such as by reductive amination using as startingmaterials a compound of the formula (II) and ammonia to prepare thecorresponding primary amine, reaction of the amine with epichlorohydrinor 1,3-dichloropropan-2-ol to prepare the corresponding azetidin-3-olderivative, followed by hydroxy functional group interconversion toprovide a compound of the formula (XVIII).

11) The compounds of the formula (I) where X, X¹, R, R¹, R² and m are aspreviously defined for Method (10) can be prepared by reductiveamination using as starting materials a compound of the formula:##STR27## where X, R, R¹ and m are as previously defined for a compoundof the formula (I), and a compound of the formula:

    HNR.sup.3 R.sup.4, (C.sub.3 -C.sub.7 cycloalkyl-C.sub.1 -C.sub.4 alkyl)R.sup.5 NH, (C.sub.3 -C.sub.7 cycloalkyl-C.sub.1 -C.sub.4 alkyl).sub.2 NH, ##STR28## , as appropriate, or an acid addition salt thereof, where W, W.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9 and n are as previously defined for a compound of the formula (I). The reaction is preferably carried out in the presence of a suitable acid, e.g. acetic acid.

A typical procedure that can be followed is described in Method (1).

If a primary amine is used, the reaction proceeds via an imineintermediate. If a secondary amine is used, the reaction proceeds via anintermediate iminium salt (cf. a compound of the formula (IIIA)). Boththe imine and iminium salts may be stable and isolatable. The reactionis preferably carried out without isolation of the imine or iminium saltintermediate in which case it is reduced in situ to provide a compoundof the formula (I).

The starting materials of the formula (XIX) can be prepared by oxidationof the corresponding azetidin-3-ol derivatives (preparation described inthe preparation of the starting materials for Method (10)) underconventional conditions, e.g. using pyridinium chlorochromate ortetrapropylammonium perruthenate as the oxidising agent.

12) The compounds of the formula (I) where R² is morpholino and X, X¹,R, R¹ and m are as previously defined for a compound of the formula (I),can be prepared by reaction of a compound of the formula (I) where R² is--NH₂ and X, X¹, R, R¹ and m are as previously defined for a compound ofthe formula (I), with bis(2-chloroethyl) ether.

In a typical procedure, a compound of the formula (I) where R² is --NH₂is reacted with bis(2-chloroethyl) ether in the presence of a suitableacid acceptor, e.g. triethylamine, and in a suitable solvent, e.g.dichloromethane.

Certain of the starting amine derivatives, i.e. 3-aminoazetidinederivatives, can be prepared by reacting a compound of the formula(XVIII) where Z⁷ is a suitable leaving group, e.g., methanesulphonyloxy,with a suitable azide, e.g. sodium azide or trimethylsilyl azide, toprovide the corresponding 3-azidoazetidine derivative, followed byreduction thereof, e.g. using sodium borohydride, to provide therequired 3-aminoazetidine derivative (see also Method (10)).

13) The compounds of the formula (I) where X, X¹, R, R¹, R² and m are aspreviously defined for a compound of the formula (I) except those whereR² is --CO₂ H, R is C₁ -C₆ alkyl substituted by --COOH, W is CHCO₂ H orW¹ is CHCO₂ H, can be prepared by reductive cyclisation of a compound ofthe formula: ##STR29## where X, X¹, R, R¹, R² and m are as previouslydefined for this Method and R¹¹ is a suitable ester-forming group, e.g.C₁ -C₄ alkyl, preferably methyl or ethyl, or benzyl.

In a typical procedure, a compound of the formula (XX) is firstgenerated in situ by reacting a compound of the formula: ##STR30## whereX, X¹, R¹, R², R¹¹ and m are as previously defined for a compound of theformula (XX), with a compound of the formula RNH₂ where R is aspreviously defined for this Method and then the reductive cyclisation isfacilitated by the presence of a suitable reducing agent, e.g. Raneynickel. The reaction is carried out in a suitable solvent, e.g. methanolor ethanol, and under an atmosphere of hydrogen.

The starting materials of the formula (XXI) can be prepared byconventional methods.

14) Certain compounds of the formula (I) can be prepared byderivatisation of certain amines of the formula (I). For example, acompound of the formula (I) wherein R² is ##STR31## wherein W is NH orCHNHR⁵, W¹ is CHNHR⁵, W² is W¹, --CH₂ W¹ --, --CH₂ WCH₂ -- or --CH₂ CH₂WCH₂ --, or R⁹ is --NHR⁵ and X, X¹, X², R, R¹, R⁵, R⁶, R⁷, m and n areas previously defined for a compound of the formula (I), may beconverted to

(a) a compound of the formula (I) wherein W is NR⁵ or CHNR⁵ R⁶, W¹ isCHNR⁵ R⁶ or R⁹ is --NHR⁵, or an acid addition salt thereof, asappropriate, wherein R⁵ and R⁶ are as previously defined for a compoundof the formula (I) with the provisos that R⁵ is not H and it has amethylene group bonded to the nitrogen atom, by reductive amination withan aldehyde of the formula (C₁ -C₃ alkyl)CHO or (C₃ -C₇ cycloalkyl-C₁-C₃ alkyl)CHO, said C₁ -C₃ alkyl and C₃ -C₇ cycloalkyl-C₁ -C₃ alkylbeing optionally substituted by fluoro.

Suitable conditions for this conversion are described in Method (1);

(b) a compound of the formula (I) wherein W is NCONHR⁶ or CHNR⁵ CONHR⁶,W¹ is CHNR⁵ CONHR⁶ or R⁹ is --NR⁵ CONHR⁶, as appropriate, wherein R⁵ andR⁶ are as previously defined for a compound of the formula (I) with theproviso that R⁶ is not H, by reaction with an isocyanate of the formula:

    R.sup.6 NCO

wherein R⁶ is as previously defined for this Method.

The reaction is typically carried out using a suitable solvent, e.g.dichloromethane or tetrahydrofuran;

(c) a compound of the formula (I) wherein W is NSO₂ CF₃ or CHNR⁵ SO₂CF₃, W¹ is CHNR⁵ SO₂ CF₃ or R⁹ is --NR⁵ SO₂ CF₃, as appropriate, whereinR⁵ is as previously defined for a compound of the formula (I), byreaction with trifluoromethanesulphonyl chloride ortrifluoromethanesulphonic anhydride, optionally in the presence of asuitable acid acceptor, e.g. triethylamine, pyridine or potassiumcarbonate. The reaction is typically carried out in a suitable organicsolvent, e.g. dichloromethane or acetonitrile;

(d) a compound of the formula (I) wherein W is NSO₂ (C₁ -C₄ alkyl),NSO₂NR⁵ R⁶, NSO₂ (morpholino), NSO₂ (aryl),CHNR⁵ (SO₂ C₁ -C₄ alkyl) or CHNR⁵SO₂ NR⁵ R⁶, W¹ is CHNR⁵ (SO₂ C₁ -C₄ alkyl) or CHNR⁵ SO₂ NR⁵ R⁶, or R⁹ is--NR⁵ (SO₂ C₁ -C₄ alkyl) or --NR⁵ SO₂ NR⁵ R⁶, as appropriate, wherein R⁵and R⁶ are as previously defined for a compound of the formula (I), byreaction with a C₁ -C₄ alkanesulphonyl chloride or bromide, a C₁ -C₄alkanesulphonic anhydride or a compound of the formula:

    R.sup.5 R.sup.6 NSO.sub.2 (Cl or Br), (morpholino)SO.sub.2 (Cl or Br) or (aryl)SO.sub.2 (Cl or Br)

, as appropriate, optionally in the presence of a suitable acidacceptor, e.g. triethylamine.

The reaction is typically carried out in a suitable organic solvent,e.g. dichloromethane, at from 0° C. to room temperature;

(e) a compound of the formula (I) wherein W is NCOR⁶ or CHNR⁵ COR⁶, W¹is CHNR⁵ COR⁶ or R⁹ is --NR⁵ COR⁶, as appropriate, wherein R⁵ and R⁶ areas previously defined for a compound of the formula (I) with the provisothat R⁶ is not H, by reaction with a compound of the formula:

    R.sup.6 CO(Cl or Br) or (R.sup.6 CO).sub.2 O

wherein R⁶ is as previously defined for this Method, optionally in thepresence of a suitable acid acceptor, e.g. triethylamine.

The reaction is typically carried out in a suitable organic solvent,e.g. dichloromethane, at from 0° C. to room temperature;

(f) a compound of the formula (I) wherein W, W¹ or R⁹ is as previouslydefined for Method 14(e), as appropriate, by condensation with acompound of the formula:

    R.sup.6 CO.sub.2 H

wherein R⁶ is as previously defined for this Method. The reaction can beperformed under conventional conditions, e.g. using 1,1'-carbonyl-diimidazole or1-hydroxybenzotriazole/1,3-dicyclohexylcarbodiimide (e.g. see Method(9)) to generate activated intermediates;

or

(g) a compound of the formula (I) where W is NSO₂ NR⁵ R⁶ or CHNR⁵ SO₂NR⁵ R⁶, W¹ is CHNR⁵ SO₂ NR⁵ R⁶ or R⁹ is --NR⁵ SO₂ NR⁵ R⁶, asappropriate, wherein R⁵ and R⁶ are as previously defined for a compoundof the formula (I), by reaction with a compound of the formula:

    R.sup.5 R.sup.6 NSO.sub.2 NH.sub.2.

The reaction is typically carried out at an elevated temperature in asuitable solvent, e.g. 1,4-dioxane.

15) The compounds of the formula (I) wherein R² is: ##STR32## wherein Wand W¹ are CHCO₂ H and W² is W¹, --CH₂ W¹ --, --CH₂ WCH₂ -- or --CH₂ CH₂WCH₂ -- and X, X¹, X², R, R¹, R², R⁵, R⁶, R⁷, m and n are as previouslydefined for a compound of the formula (I), may be prepared by hydrolysisof a compound of the formula (I) wherein

W and W¹ are CHCO₂ (C₁ -C₄ alkyl), W² is W¹, --CH₂ W¹ --, --CH₂ WCH₂ --or --CH₂ CH₂ WCH₂ -- and X, X¹, X², R, R¹, R², R⁵, R⁶ R⁷, m and n are aspreviously defined for a compound of the formula (I). Preferably, W andW are CHCO₂ CH₃ or CH₂ CO₂ CH₂ CH₃.

The hydrolysis is typically carried out using an aqueous solution of asuitable acid or base, e.g. a mineral acid such as hydrochloric orsulphuric acid or a base such as sodium or potassium hydroxide,optionally in the presence of a suitable organic co-solvent, e.g.methanol or ethanol.

16) The compounds of the formula (I) wherein R² is ##STR33## wherein Wand W¹ are CHNR⁵ R⁶, W² is W¹, --CH₂ W¹ --, --CH₂ WCH₂ -- or --CH₂ CH₂WCH₂ --, R⁹ is --NR⁵ R⁶ and X, X¹, X², R, R¹, R², R⁵, R⁶, R⁷, m and nare as previously defined for a compound of the formula (I) may beprepared by reaction of a compound of the formula: ##STR34## wherein R¹²is ##STR35## wherein W^(B) and W^(1B) are CHZ⁸, W^(2B) is W^(1B), --CH₂W^(1B) --, --CH₂ W^(B) CH₂ -- or --CH₂ CH₂ W^(B) CH₂ --, Z⁸ is asuitable leaving group, e.g. halo, (preferably chloro or bromo),methanesulphonyloxy, trifluoromethanesulphonyloxy orp-toluenesulphonyloxy, and X, X¹, X², R, R¹, R⁵, R⁶, R⁷, m and n are aspreviously defined for a compound of the formula (I), with a compound ofthe formula:

    HNR.sup.5 R.sup.6

wherein R⁵ and R⁶ are as previously defined for a compound of theformula (I), optionally in the presence of a suitable additional acidacceptor, e.g. triethylamine or potassium carbonate.

The reaction is typically carried out in a suitable solvent such asacetonitrile.

17) The compounds of the formula (I) wherein R² is ##STR36##

W and W¹ are CHNR⁵ R⁶ and X, X¹, X², R, R¹, R⁵, R⁶, R⁷, m and n arepreviously defined for a compound of the formula (I), may be prepared byreductive amination using as the starting materials a compound of theformula (I): wherein R² is ##STR37## and X, X¹, X², R, R¹, R⁵, R R⁷, mand n are as previously defined for a compound of the formula (I), and acompound of the formula:

    HNR.sup.5 R.sup.6

wherein R⁵ and R⁶ are as previously defined for a compound of theformula (I).

Conventional conditions are used such as those described for Method (1).Again, the intermediate imine or iminium salt formed may be stable orisolatable. The reaction is preferably carried out without isolation ofthis intermediate in which case it is reduced in situ to provide acompound of the formula (I).

18) All the compounds of the formula (I) may be prepared byintramolecular cyclisation of a compound of the formula: ##STR38##wherein X, X¹, R, R¹, R² and m are as previously defined for a compoundof the formula (I) and Z⁹ is a suitable leaving group, e.g. halo(preferably chloro or bromo), methanesulphonyloxy orp-toluenesulphonyloxy, optionally in the presence of a suitable acidacceptor, e.g. triethylamine.

The reaction is typically carried out in a suitable solvent, e.g.dichloromethane.

19) All the compounds of the formula (I) except those where m is 0 maybe prepared by catalysed carbonyl addition-cyclisation of a compound ofthe formula: ##STR39## wherein t is 0 or 1 and X, X¹, R, R¹ and R² areas previously defined for a compound of the formula (I).

The reaction is typically carried out under an atmosphere of carbonmonoxide using a suitable catalyst, e.g.tetrakistriphenylphosphinepalladium(0), a suitable base, e.g.triethylamine, and in a suitable organic solvent, e.g. tetrahydrofuran,at about room temperature.

All of the above reactions and the preparations of novel startingmaterials used in the preceding methods are conventional and appropriatereagents and reaction conditions for their performance or preparation aswell as procedures for isolating the desired products will be well knownto those skilled in the art with reference to literature precedents andthe Examples and Preparations hereto.

A pharmaceutically acceptable acid addition or base salt of a compoundof the formula (I) may be readily prepared by mixing together solutionsof a compound of the formula (I) and the desired acid or base, asappropriate. The salt may precipitate from solution and be collected byfiltration or may be recovered by evaporation of the solvent.

The affinity of the compounds of formula (I) and their salts for thehuman NK₁ receptor can be tested in vitro by testing their ability toinhibit [³ H]-Substance P binding to membranes prepared from the humanIM9 cell line expressing the human NK₁ receptor using a modification ofthe method described in McLean, S. et al, J. Pharm. Exp. Ther., 267,472-9 (1993) in which whole cells were used.

The affinity of the compounds of formula (I) and their salts for thehuman NK₂ receptor can be tested in vitro by testing their ability tocompete with [³ H] or [¹²⁵ I]NKA (neurokinin A) for binding to membranesprepared from Chinese hamster ovary cells expressing the cloned humanNK₂ receptor. In this method, washed Chinese hamster ovary cellmembranes are prepared as described for the previous method where IM9cells are used instead. The membranes are incubated (90 min, 25° C.)with [³ H] NKA and with a range of concentrations of the test compound.Non-specific binding was determined in the presence of 10 μM NKA.

The NK₂ receptor antagonist activity of the compounds of the formula (I)can be tested, in vitro, by testing their ability to antagonise thecontractile effects of the selective NK₂ receptor agonist [βAla⁸]NKA.sub.(4-10) in the rabbit pulmonary artery, using the method ofPatacchini and Maggi, Eur. J. Pharmacol., 236, 31-37 (1993).

The compounds of the formula (I) and their salts can be tested for Nk₂receptor antagonist activity, in vivo, by testing their ability toinhibit bronchoconstriction induced by [βAla⁸ ]NKA.sub.(4-10) in theanaesthetised guinea pig, using the method described by Murai et al, J.Pharm. Exp. Ther., 262, 403-408 (1992) or Metcalfe et al, Br. J.Pharmacol., 112, 563P (1994).

The compounds of the formula (I) and their salts can be tested for NK₃receptor antagonist activity, in vitro, by testing their ability toantagonise the contractile effects of the selective NK₃ receptor agonistsenktide in the guinea-pig ileum using the method of Maggi et al, Br. J.Pharmacol., 101, 996-1000 (1990).

For human use, the compounds of the formula (I) and their salts can beadministered alone, but will generally be administered in admixture witha pharmaceutically acceptable diluent or carrier selected with regard tothe intended route of administration and standard pharmaceuticalpractice. For example, they can be administered orally, includingsublingually, in the form of tablets containing such excipients asstarch or lactose, or in capsules or ovules either alone or in admixturewith excipients, or in the form of elixirs, solutions or suspensionscontaining flavouring or colouring agents. They can be injectedparenterally, for example, intravenously, intramuscularly orsubcutaneously. For parenteral administration, they are best used in theform of a sterile aqueous solution which may contain other substances,for example, enough salts or glucose to make the solution isotonic withblood.

For oral and parenteral administration to human patients, the dailydosage level of the compounds of the formula (I) and their salts will befrom 0.001 to 20, preferably from 0.01 to 20, more preferably from 0.5to 5, and most preferably from 1 to 2, mg/kg (in single or divideddoses). Thus tablets or capsules of the compounds will contain from 0.1to 500, preferably from 50 to 200, mg of active compound foradministration singly or two or more at a time, as appropriate. Thephysician in any event will determine the actual dosage which will bemost suitable for an individual patient and it will vary with the age,weight and response of the particular patient. The above dosages areexemplary of the average case; there can, of course, be individualinstances where higher or lower dosage ranges are merited, and such arewithin the scope of this invention.

Alternatively, the compounds of the formula (I) can be administered byinhalation or in the form of a suppository or pessary, or they may beapplied topically in the form of a lotion, solution, cream, ointment ordusting powder. An alternative means of transdermal administration is byuse of a skin patch. For example, they can be incorporated into a creamconsisting of an aqueous emulsion of polyethylene glycols or liquidparaffin; or they can be incorporated, at a concentration between 1 and10%, into an ointment consisting of a white wax or white soft paraffinbase together with such stabilizers and preservatives as may berequired.

It is to be appreciated that reference to treatment includes prophylaxisas well as the alleviation of established symptoms of the disease.

Thus the invention further provides:

i) a pharmaceutical composition comprising a compound of the formula(I), or a pharmaceutically acceptable salt thereof, together with apharmaceutically acceptable diluent or carrier;

ii) a compound of the formula (I), or a pharmaceutically acceptable saltor composition thereof, for use as a medicament;

iii) the use of a compound of the formula (I), or of a pharmaceuticallyacceptable salt or composition thereof, for the manufacture of amedicament for the treatment of a disease by producing an antagonisteffect on a tachykinin acting at the human NK₁, NK₂ or NK₃ receptor, ora combination thereof;

iv) use as in (iii) where the disease is an inflammatory disease such asarthritis, psoriasis, asthma or inflammatory bowel disease, a centralnervous system (CNS) disorder such as anxiety, depression, dementia orpsychosis, a gastrointestinal (GI) disorder such as functional boweldisease, irritable bowel syndrome, gastro-oesophageal reflux, faecalincontinence, colitis or Crohn's disease, an urogenital tract disordersuch as incontinence, hyperreflexia or cystitis, a pulmonary disordersuch as chronic obstructive airways disease, an allergy such as eczema,contact dermatitis or rhinitis, a hypersensitivity disorder such aspoison ivy, a peripheral neuropathy such as diabetic neuropathy,neuralgia, causalgia, painful neuropathy, a burn, herpetic neuralgia orpost-herpetic neuralgia, cough or acute or chronic pain;

v) a method of treatment of a human to treat a disease by producing anantagonist effect on a tachykinin acting at the human NK₁, NK₂ or NK₃receptor, or a combination thereof, which comprises treating said humanwith an effective amount of a compound of the formula (I) or with apharmaceutically acceptable salt or composition thereof;

vi) a method as in (v) where the disease is an inflammatory disease suchas arthritis, psoriasis, asthma or inflammatory bowel disease, a centralnervous system (CNS) disorder such as anxiety, depression, dementia orpsychosis, a gastrointestinal (GI) disorder such as functional boweldisease, irritable bowel syndrome, gastro-oesophageal reflux, faecalincontinence, colitis or Crohn's disease, an urogenital tract disordersuch as incontinence, hyperreflexia or cystitis, a pulmonary disordersuch as chronic obstructive airways disease, an allergy such as eczema,contact dermatitis or rhinitis, a hypersensitivity disorder such aspoison ivy, a peripheral neuropathy such as diabetic neuropathy,neuralgia, causalgia, painful neuropathy, a bum, herpetic neuralgia orpost-herpetic neuralgia, cough or acute or chronic pain; vii) a compoundof the formula (II), (IIIA), (XII), (XIV), (XV), (XVI), (XVII), (XVIII),(XIX), (XX), (XXI), (XXII), (XXIII) or (XXIV).

The following Examples illustrate the preparation of the compounds ofthe formula (I):

(REFERENCE) EXAMPLE 15-(3,4-Dichlorophenyl)-5-(2-[3-morpholinoazetidin-1-y]ethyl)-2(1H)-piperidone##STR40##

To a solution of the aldehyde (see Preparation 6) (150 mg, 0.52 mmol)and 3-morpholinoazetidine hydrochloride (see Preparation 56) (103 mg,1.1 mol. equiv.) in tetrahydrofuran (7.5 ml) under nitrogen was addedtriethylamine (0.08 ml, 1.1 mol. equiv.). After one hour, sodiumtriacetoxyborohydride (171 mg 1.5 mol. equiv.) was added followedimmediately by glacial acetic acid (0.03 ml) and the mixture was stirredfor 2 hours. Water (1 ml) was then added followed by saturated aqueoussodium bicarbonate solution (10 ml), the mixture was extracted withdichloromethane (30×20 ml) and the combined organic layers dried overmagnesium sulphate. The solution was filtered, the solvent removed fromthe filtrate under reduced pressure and the residue initiallychromatographed on silica gel eluting with a solvent gradient ofmethanol:ethyl acetate (1:9 to 1:4, by volume) to remove majorimpurities and then rechromatographed using silica gel eluting withmethanol:dichloromethane (1:9, by volume) to give the title compound (78mg). TLC R_(f) =0.27 (silica, methanol:dichloromethane, 1:9, by volume).LRMS m/z=411 (m+1)⁺. Found: C, 57.57; H, 6.76; N, 9.78. C₂₀ H₂₇ Cl₂ N₃O₂.0.05 CH₂ Cl₂ requires C, 57.81; H, 6.56: N, 10.09%.

¹ H-NMR (CDCl₃)δ=1.60-1.70 (m,1H), 1.80-1.85 (m,1H), 2.00-2.40 (m, 10H),2.65-2.75 (m,2H), 2.85-2.90 (m, 1H), 3.35-3.40 (m,3H), 3.65-3.75 (m,5H),6.20 (s, br., 1H), 7.15-7.50 (m,3H) ppm.

EXAMPLES 2 to 59

The compounds of the following tabulated Examples of the generalformula: ##STR41## were prepared by a similar method to that of Example1 using the appropriate aldehyde (see Preparations 39 to 43, 137 to 140and 187 to 191) and azetidine (see Preparations 56, 61, 65, 66, 67, 70,77 to 80, 82, 84, 85, 87, 89, 107 to 118, 121, 134, 154, 180 and 181)starting materials.

    __________________________________________________________________________    Ex.                                           LRMS                            No.   R           R.sup.1                                                     x.sup.1 -R.sup.2                                                                    m.p.        m/z        Analysis/.sup.1 H-NMR                            __________________________________________________________________________     2.sup.1                                                                            1 #STR42##                                                                                8 #STR43##                                                                               2 #STR44##    -- 518/520 (m                                                                         Found: C, 60.88; H,                                                           6.29; N, 7.69.                                                                C.sub.27 H.sub.33                                                             N.sub.3 Cl.sub.2                                                              OS.0.25 CH.sub.2                                                              Cl.sub.2 requires C,                                                          60.63; H, 6.26, N,                                                            7.78%.                                                                        .sup.1 H-NMR(CDCl.sub.3                                                       ): δ = 1.4-                                                             1.6(m,1H),                                                                    1.6-1.8(m,1H),                                                                2.0-2.2(m,5H), 2.3-2.5                                                        (m,5H), 2.5-2.7(m,6H),                                                        2.8-3.0(m,1H),                                                                3.1-3.3(m,1H),                                                                3.25-3.5(m,3H), 4.4                                                           (d,1H), 4.8(d,1H),                                                            6.7-6.9(m,1H), 7.05                                                           (s, 1H), 7.4-7.2(m,6H)                                                        ppm.                        3.sup.1,2                                                                          1 #STR45##                                                                                8 #STR46##                                                                               3 #STR47##    -- 534 (m + 1).sup.+                                                                  Found: C, 57.91; H,                                                           5.77; N, 7.58.                                                                C.sub.27 H.sub.33                                                             N.sub.3 Cl.sub.2                                                              O.sub.2 S.0.37CH.sub.2                                                        Cl.sub.2 requires C,                                                          58.05; H, 6.01,  N,                                                           7.42%.                                                                        .sup.1 H-NMR(CDCl.sub.3                                                       ): δ = 1.1-                                                             1.3(m,1H),                                                                    1.4-1.8(m,1H),                                                                1.9-2.3(m,5H), 2.4-2.6                                                        (m,5H), 2.6-2.7(m,6H),                                                        2.7-2.9(m,1H), 2.9-3.1                                                        (m,1H), 3.2-3.4(m,2H),                                                        3.4-3.6(m,1H), 4.4                                                            (d,1H), 4.8(d,1H), 6.8                                                        (d,1H), 7.1(s, 1H),                                                           7.3-7.4(m,6H) ppm.          4                                                                                  1 #STR48##                                                                                8 #STR49##                                                                               4 #STR50##    -- 551 (m + 1).sup.+                                                                  Found: C, 54.96; H,                                                           5.72; N, 6.96.                                                                C.sub.27 H.sub.33                                                             N.sub.3 Cl.sub.2                                                              O.sub.2 S.0.63CH.sub.2                                                        Cl.sub.2 requires C,                                                          54.96; H, 5.72,  N,                                                           6.96%.                                                                        .sup.1 H-NMR(CDCl.sub.3                                                       ): δ = 1.4-1.8(m,                                                       3H),                                                                          1.9-2.2(m,5H),2.4-2.55                                                        (m,1H), 2.6(q, 2H),                                                           2.7-2.8(m,4H), 3.0-3.1                                                        (m,5H), 3.2-3.4(m,2H),                                                        3.5-3.6(m,1H),                                                                4.4(d,1H), 4.8(d,1H),                                                         6.7(d,1H), 7.1 (s,                                                            1H), 7.3-7.5(m,6H)                                                            ppm.                        5                                                                                  1 #STR51##                                                                                8 #STR52##                                                                               5 #STR53##    -- 579 (m + 1).sup.+                                                                  Found: C, 67.36; H,                                                           6.33; N, 6.81.                                                                C.sub.33 H.sub.37                                                             N.sub.3 Cl.sub.2                                                              O.sub.2.0.125CH.sub.2                                                         Cl.sub.2 requires C,                                                          67.52; H, 6.37; N,                                                            7.13%.                                                                        .sup.1 H-NMR(CDCl.sub.3                                                       ): δ = 1.4-1.6(m,                                                       2H), 1.6-1.8 (m,1H),                                                          2.0-2.2(m,6H),                                                                2.3-2.45(m,1H),                                                               2.5-2.7 (m,1H),                                                               3.2-3.4(m,3H),                                                                2.8-3.0(m,1H), 3.2-3.4                                                        (m,3H), 3.4-3.6(m,1H),                                                        3.8(t, 1H), 3.9-4.05                                                          (m,1H), 4.4(d,1H), 4.5                                                        (d,1H), 4.8(d,1H),                                                            6.8(d,1H),  7.05(s,                                                           1H), 7.25-7.5 (m,11H)                                                         ppm.                        6.sup.1                                                                            1 #STR54##                                                                                8 #STR55##                                                                               6 #STR56##    -- 517 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3                                                       ): δ =                                                                  1.4-1.8(m,4H), 1.7-1.9                                                        (m,2H), 2.0-2.2(m,6H),                                                        2.3-2.5(m,2H), 2.5-2.7                                                        (m,2H), 3.1(t, 1H),                                                           3.2 (d,1H),                                                                   3.3-3.45(m,2H), 3.5(t,                                                        1H), 3.7(d,2H),                                                               3.8(m,2H), 4.4(d,1H),                                                         4.8(d,1H), 6.8(d,1H),                                                         7.1(s, 1H), 7.3(m,6H)                                                         ppm.                        7                                                                                  1 #STR57##                                                                                8 #STR58##                                                                               7 #STR59##    -- 602 (m + 1).sup.+                                                                  Found: C, 62.28; H,                                                           7.10; N, 8.84.                                                                C.sub.32 H.sub.42                                                             N.sub.4 Cl.sub.2                                                              O.sub.3.0.25CH.sub.2                                                          Cl.sub.2 requires C,                                                          62.18; H, 6.88; N,                                                            9.00%. .sup.1 H-NMR                                                           (CDCl.sub.3): δ                                                         = 1.3-1.5 (m,9H),                                                             1.5-1.7(m,4H),                                                                1.9-2.1(m,4H), 2.1-2.3                                                        (m,6H), 2.4-2.6(m,1H),                                                        2.6-2.8(m,2H),                                                                2.7-2.9(m,1H),                                                                3.3-3.5(m,4H),                                                                3.5(d,1H), 4.4(d,1H),                                                         4.8(d,1H), 6.8(d,1H),                                                         7.1(s, 1H),                                                                   7.2-7.4(m,6H)  ppm.         8.sup.1                                                                            1 #STR60##                                                                                8 #STR61##                                                                               8 #STR62##    -- 505 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3                                                       ): δ =                                                                  2.1-2.3(m,8H), 2.3-2.5                                                        (m,3H), 2.9-3.1(m,2H),                                                        3.3(s, 3H), 3.3-3.5                                                           (m,6H), 3.4-3.6(m,1H),                                                         3.7-3.9(m,2H), 4.3                                                           (d,1H), 4.9(d,1H),                                                            6.8(d,1H), 7.1(s, 1H),                                                        7.2-7.4 (m,6H) ppm.         9.sup.1                                                                            1 #STR63##                                                                                8 #STR64##                                                                               9 #STR65##    -- 516 (m + 1).sup.+                                                                  Found: C, 63.46; H,                                                           7.04; N, 10.87.                                                               C.sub.28 H.sub.36                                                             N.sub.4 Cl.sub.2                                                              O.0.25CH.sub.2                                                                Cl.sub.2 requires C,                                                          63.21; H, 6.85;  N,                                                           10.44%. .sup.1                                                                H-NMR(CDCl.sub.3):                                                            δ = 1.4-1.6(m,1H)                                                       ,  1.8-2.5(m,21H),                                                            2.8-2.9 (m,1H),                                                               3.3(d,1H), 3.5 (s,                                                            1H), 3.55-3.6(m,1H),                                                          4.4(d,1H), 4.9(d,1H),                                                         6.8(d,1H), 7.1(s, 1H),                                                         7.2-7.4(m,6H) ppm.        10                                                                                  1 #STR66##                                                                                8 #STR67##                                                                               0 #STR68##    -- 517 (m + 1).sup.+                                                                  Found: C, 60.87; H,                                                           5.91; N,  7.82.                                                               C.sub.27 H.sub.31                                                             N.sub.3 Cl.sub.2                                                              O.sub.3.0.25CH.sub.2                                                          Cl.sub.2 requires C,                                                          60.47; H, 5.92;  N,                                                           7.70%..sup.1 H-NMR(CDCl                                                       .sub.3):  δ                                                             =1.5-1.7(m,1H),                                                               2.0-2.2 (m,2H),                                                               2.3-2.6(m,5H),                                                                2.8-3.0(m,2H),                                                                3.3(d,1H),                                                                    3.3-3.5(m,4H), 3.5-3.6                                                        (m,1H), 3.8-4.0(m,2H),                                                         4.2(s, 2H),                                                                  4.4(d,1H),                                                                    4.8-4.9(m,2H),                                                                6.75-6.85 (m,1H),                                                             7.1(s, 1H), 7.2-7.5                                                           (m,6H) ppm.                11.sup.1                                                                            1 #STR69##                                                                                8 #STR70##                                                                               1 #STR71##    -- 529 (m + 1).sup.+                                                                  Found: C, 66.10; H,                                                           7.10; N,                                                                      7.44.C.sub.30 H.sub.39                                                        N.sub.3 Cl.sub.2 O.                                                           0.25CH.sub.2 Cl.sub.2                                                         requires C, 66.08; H,                                                         7.24;  N, 7.64%.                                                              .sup.1 H-NMR(CDCl.sub.3                                                       ):  δ =                                                                 0.8-1.0(m,6H),                                                                1.2-1.8(m,10H),                                                               1.95-2.2(m,4H),                                                               2.4-2.9(m,2H), 3.2-3.3                                                        (m,1H), 3.3-3.7(m,6H),                                                         4.4(d,1H),                                                                   4.85(d,1H),                                                                   6.8(d,1H), 7.1(s, 1H),                                                         7.2-7.4(m,6H) ppm.        12.sup.1,4                                                                          1 #STR72##                                                                                8 #STR73##                                                                               2 #STR74##    -- 529 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3                                                       ): δ =                                                                  1.6-1.7(m,1H), 1.7-2.0                                                        (m,2H),                                                                       2.05-2.4(m,4H),                                                               2.45-2.65(m,1H), 3.1-                                                         3.2(m,2H),                                                                    3.25-3.35(m,1H),                                                              3.6-3.8(m,3H),                                                                4.45(d,1H),                                                                   4.6-4.7(m,1H), 4.85                                                           (d,1H), 6.8(d,1H),                                                            7.05-7.2 (m,2H),                                                              7.25-7.5(m ,7H),                                                              7.6(s, 1H) ppm.            13                                                                                  1 #STR75##                                                                                8 #STR76##                                                                               3 #STR77##    -- 502 (m + 1).sup.+                                                                  Found: C, 64.31; H,                                                           6.86; N,  8.15.                                                               C.sub.27 H.sub.33                                                             N.sub.3 Cl.sub.2                                                              O.sub.2  requires C,                                                          64.52; H, 6.62; N,                                                            8.36%.                                                                        .sup.1 H-NMR(CDCl.sub.3                                                       ): δ =                                                                  1.5-1.7(m,1H), 1.7-                                                           1.9(m,1H), 1.9-2.35                                                           (m,9H),                                                                       2.35-2.5(m,1H),                                                               2.6-2.7(m,2H), 2.9(t,                                                         1H),  3.2(d,1H),                                                              3.3-3.45 (m,2H),                                                              3.5(d,1H), 3.6-                                                               3.7(m,4H), 4.4(d,1H),                                                         4.9(d,1H), 6.7(d,1H),                                                         7.1(s, 1H), 7.3-7.5                                                           (m,6H) ppm.                14                                                                                  1 #STR78##                                                                                9 #STR79##                                                                               4 #STR80##    -- 502 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3                                                       ): δ =                                                                  1.4-1.8(m,3H),                                                                1.9-2.2(m,5H),                                                                2.4-2.6(m,5H),                                                                2.6-2.9(m,6H),                                                                3.2-3.4(m,4H), 4.4                                                            (d,1H), 4.8(d,1H),                                                            6.6-6.8(m,2H), 7.0 (q,                                                        1H), 7.2-7.4(m,5H),                                                           ppm.                       15.sup.1                                                                            3 #STR81##                                                                                9 #STR82##                                                                               5 #STR83##    -- 435 (m).sup.+                                                                      .sup.1 H-NMR(CDCl.sub.3                                                       ): δ =                                                                  0.9-1.1(m,3H), 1.2-1.4                                                        (m,4H), 1.7-1.9(m,8H),                                                         2.1-2.35(m,9H),                                                              2.6-2.8(m,2H),                                                                2.8-3.0(m,1H), 3.1-3.2                                                        (m,1H),                                                                       3.3-3.45(m,4H),                                                               3.7-3.9(m,4H), 6.9-                                                           7.1(m,3H) ppm.             16.sup.1                                                                            1 #STR84##                                                                                9 #STR85##                                                                               6 #STR86##    -- 468 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3                                                       ): δ =                                                                  1.2-1.6(m,8H), 1.9-                                                           2.2(m,9H),                                                                    2.3-2.5(m,1H),                                                                2.5-2.7(m,2H), 2.7-2.9                                                        (m,1H), 3.2(d,1H),                                                            3.3- 3.5(m,2H),                                                               3.5(d,1H), 4.4(d,1H),                                                         4.8 (d,1H), 6.6(s,                                                            1H),  6.6-6.8(m,1H),                                                          7.0 (m,1H),                                                                   7.2-7.3(m,5H)  ppm.        17.sup.1                                                                            1 #STR87##                                                                                8 #STR88##                                                                               7 #STR89##    -- 518/520 (m                                                                         Found: C, 62.20; H,                                                           6.67; N,                                                                      7.44.C.sub.28 H.sub.37                                                        N.sub.3 Cl.sub.20 O.                                                          0.31CH.sub.2 Cl.sub.2                                                         requires C, 62.39; H,                                                         6.96; N,7.71%. .sup.1                                                         H-NMR(CDCl.sub.3):                                                            δ = 1.1 (s, 6H),                                                        1.5-1.6(m,1H),                                                                1.6-1.8(m,1H),                                                                1.9-2.3(m,11H),                                                               2.4-2.5(m,1H),                                                                2.6-2.7(m,2H),                                                                3.l-3.2(m,1H),                                                                3.2-3.4(m,3H),                                                                3.6(d,1H), 4.4 (d,1H),                                                        4.85(d,1H),                                                                   6.8(d,1H), 7.1(s, 1H),                                                         7.2-7.4(m,6H) ppm.        18.sup.1                                                                            1 #STR90##                                                                                0 #STR91##                                                                               8 #STR92##    -- 468 (m + 1).sup.+                                                                  Found: C, 66.66; H,                                                           7.30; N, 8.61.                                                                C.sub.27 H.sub.34                                                             N.sub.3 ClO.sub.2.H.sub                                                       .2 O requires C,                                                              66.70; H, 7.50; N,                                                            8.60%.                                                                        .sup.1 H-NMR(CDCl.sub.3                                                       ): δ = 1.45-1.9                                                         (m,4H), 2.0-2.6(m,8H),                                                        2.6-2.8 (m,3H),                                                               2.8-3.0(m,1H), 3.5-3.8                                                        (m,5H), 4.5(d,1H),                                                            4.8(d,1H), 6.9 (d,1H),                                                        7.0(s, 1H),                                                                   7.1-7.5(m,7H) ppm.         19.sup.1                                                                            1 #STR93##                                                                                1 #STR94##                                                                               8 #STR95##    -- 468 (m + 1).sup.+                                                                  Found: C, 67.46; H,                                                           7.47; N,  8.77.                                                               C.sub.27 H.sub.34                                                             N.sub.3 ClO.sub.2.                                                            0.66H.sub.2 O requires                                                        C, 67.60;  H, 7.40; N,                                                        8.80%. .sup.1 H-NMR                                                           (CDCl.sub.3): δ                                                         = 1.5-1.6 (m,1H),                                                             1.7-1.8(m,1H),                                                                1.9-2.2(m,9H),                                                                2.2-2.3(m,1H),                                                                2.6-2.7(m,2H),                                                                2.8-3.0(m,1H),                                                                3.2-3.4(m,3H),                                                                3.5-3.6(m,1H),                                                                3.7-3.8(m,4H), 4.4                                                            (d,1H), 4.8(d,1H),                                                            6.9(d,2H), 7.2(d,2H),                                                         7.2-7.4(m,5H) ppm.         20.sup.1                                                                            1 #STR96##                                                                                8 #STR97##                                                                               9 #STR98##    -- 543 (m + 1).sup.+                                                                  Found: C, 62.48; H,                                                           6.32; N,                                                                      9.70.C.sub.29 H.sub.36                                                        N.sub.4 Cl.sub.2                                                              O.sub.2. 0.25CH.sub.2                                                         Cl.sub.2 requires C,                                                          62.20; H, 6.51;  N,                                                           9.92%. .sup.1 H-NMR                                                           (CDCl.sub.3): δ                                                         = 1.45-1.8 (m,2H),                                                            1.9-2.3(m,12H),                                                               2.4-2.5(m,1H),                                                                2.6-2.7(m,2H),                                                                2.8-2.9(m,1H),                                                                3.1-3.4(m,3H),                                                                3.4-3.6(m,5H), 4.4                                                            (d,1H), 4.8(d,1H),                                                            6.8-7.4(m,8H) ppm.         21.sup.1                                                                            1 #STR99##                                                                                8 #STR100##                                                                              0 #STR101##   -- 578 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3                                                       ): δ =                                                                  1.45-1.8(m,2H),                                                               1.9-2.15(m,5H),                                                               2.3-2.5(m,5H),                                                                2.6-2.95(m,16H),                                                              3.2-3.35(m,7H),                                                               3.5-3.6(m,1H),                                                                4.4(d,1H), 4.8(d,1H),                                                         6.8-7.4(m,8H) ppm.         22                                                                                  1 #STR102##                                                                               9 #STR103##                                                                              1 #STR104##   -- 470 (m + 1).sup.+                                                                  Found: C, 65.52; H,                                                           6.89;  N, 8.34.                                                               C.sub.27 H.sub.33                                                             N.sub.3 F.sub.2                                                               O.sub.2. 0.38CH.sub.2                                                         Cl.sub.2 requires  C,                                                         65.57; H, 6.78; N,                                                            8.38%. .sup.1 H-NMR                                                           (CDCl.sub.3): δ                                                         = 1.45-1.8 (m,2H),                                                            1.95-2.3(m,9H),                                                               2.4-2.5(m,1H),                                                                2.6-2.7(m,2H),                                                                2.8-2.95(m,1H),                                                               3.2-3.4(m,3H),                                                                3.5-3.6(m,1H),                                                                3.65-3.75(m,4H), 4.4                                                          (d,1H), 4.8(d,1H),                                                            6.6-6.8(m,2H),                                                                6.95-7.05(m,1H),                                                              7.25-7.4(m,5H) ppm.        23                                                                                  1 #STR105##                                                                               8 #STR106##                                                                              2 #STR107##   -- 532/534 (m                                                                         Found: C, 60.49; H,                                                           6.50; N, 6.57.                                                                C.sub.28 H.sub.35                                                             N.sub.3 Cl.sub.2                                                              O.sub.3.0.38CH.sub.2                                                          Cl.sub.2 requires C,                                                          60.39; H, 6.39; N,                                                            7.45%.                                                                        .sup.1 H-NMR(CDCl.sub.3                                                       ): δ = 1.45-1.8                                                         (m,3H), 1.9-2.2(m,4H),                                                        2.2-2.5 (m,1H), 2.9(s,                                                        3H), 2.95-3.1 (m,2H),                                                         3.2-3.6(m,12H), 4.4                                                           (d,1H), 4.85(d,1H),                                                           6.75-6.8 (m,1H),                                                              7.05-7.1(m,1H),                                                               7.2-7.4 (m,6H) ppm.        24.sup.3                                                                            1 #STR108##                                                                               8 #STR109##                                                                              3 #STR110##   -- --   Found: C, 63.29; H,                                                           6.19; N,                                                                      7.20.C.sub.32 H.sub.39                                                        Cl.sub.2 N.sub.3                                                              O.sub.3. 0.31CH.sub.2                                                         Cl.sub.2 requires  C,                                                         63.72; H, 6.88; N,                                                            6.91%..sup.1 H-NMR                                                            (CDCl.sub.3): δ                                                         = 1.55-2.2 (m,18H),                                                           2.4-2.5(m,1H),                                                                2.55-2.7(m,2H),                                                               2.95-3.05(m,2H),                                                              3.1-3.2(m,1H),                                                                3.2-3.35(m,3H),                                                               3.55-3.6(m,1H),                                                               4.35(d,1H), 4.85-4.95                                                         (m,2H),                                                                       6.75-6.8(m,1H),                                                               7.05(d,1H),                                                                   7.2-7.35(m,6H) ppm.        25                                                                                  1 #STR111##                                                                               8 #STR112##                                                                              4 #STR113##   -- 491 (m + 1).sup.+                                                                  Found: C, 61.03; H,                                                           6.20; N, 7.62.                                                                C.sub.26 H.sub.33                                                             Cl.sub.2 N.sub.3                                                              O.sub.2 .0.38CH.sub.2                                                         Cl.sub.2  requires C,                                                         60.65; H, 6.51; N,                                                            8.05%.                                                                        .sup.1 H-NMR(CDCl.sub.3                                                       ): δ = 1.51-1.8                                                         (m,2H),                                                                       1.9-2.25(m,9H),                                                               2.35-2.5(m,3H),                                                               2.6-2.7(m,2H),                                                                3.05-3.1(m,1H),                                                               3.25-3.3(m,1H),                                                               3.4-3.45(m,2H),                                                               3.55-3.6(m,3H),                                                               4.35(d,1H),                                                                   4.85(d,1H),                                                                   6.75-6.8(m,1H),                                                               7.05(d,1H), 7.25-7.4                                                          (m,6H), ppm.               26.sup.1                                                                            1 #STR114##                                                                               8 #STR115##                                                                              5 #STR116##   -- 516 (m + 1).sup.+                                                                  Found: C, 60.00; H,                                                           6.06; N,                                                                      6.70.C.sub.28 H.sub.35                                                        Cl.sub.2 N.sub.3                                                              O.sub.2. 0.69CH.sub.2                                                         Cl.sub.2 requires C,                                                          59.93; H, 6.38; N,                                                            7.31%.                                                                        .sup.1 H-NMR(CDCl.sub.3                                                       ): δ =                                                                  1.45-2.35(m,16H),                                                             2.4-2.5(m,1H),                                                                2.6-2.7(m,2H),                                                                2.85-2.95(m,1H),                                                              3.2-3.3(m,1H),                                                                3.35-3.45(m,2H),                                                              3.5-3.6(m,1H),                                                                3.75-3.8(m,1H),                                                               4.4(d,1H), 4.85(d,1H),                                                        6.75-6.8(m,1H),                                                               7.05(d,1H), 7.25-7.45                                                         (m,6H) ppm.                27.sup.1                                                                            1 #STR117##                                                                               8 #STR118##                                                                              6 #STR119##   -- 501 (m).sup.+                                                                      Found: C, 62.42, H,                                                           6.49; N, 7.52.C.sub.27                                                        H.sub.33 Cl.sub.2                                                             N.sub.3 O.sub.2.                                                              0.25CH.sub.2 Cl.sub.2                                                         requires C,  62.49;                                                           H,1 6.45; N, 8.02%.                                                           .sup.1 H-NMR(CDCl.sub.3                                                       ): δ =                                                                  1.5-1.8(m,3H),                                                                1.95-2.3(m,8H),                                                               2.4-2.6(m,3H),                                                                2.7-2.85(m,3H),                                                               3.05-3.1(m,1H),                                                               3.2-3.4(m,3H),                                                                3.5-3.6(m,1H),                                                                4.35(d,2H),                                                                   4.85(d,1H), 6.75-                                                             6.8(m,1H), 7.1(d,1H),                                                         7.3-7.4(m,6H),  ppm.       28.sup.1                                                                            1 #STR120##                                                                               8 #STR121##                                                                              7 #STR122##   -- 517 (m + 1).sup.+                                                                  Found: C, 60.64; H,                                                           6.75; N, 7.39.C.sub.28                                                        H.sub.35 Cl.sub.2                                                             N.sub.3 O.sub.2.                                                              0.56CH.sub.2 Cl.sub.2                                                         requires C, 60.79; H,                                                         6.45; N, 7.47%. .sup.1                                                        H-NMR(CDCl.sub.3):                                                            δ =                                                                     1.3-2.7(m,20H),                                                               2.95(br.s, 1H),                                                               3.2-3.43 (m,2H),                                                              3.5-3.75(m,2H),                                                               4.4(d,1H), 4.8(d,1H),                                                         6.75-6.8(m,1H),                                                               7.1(d,1H), 7.25-7.4                                                           (m,6H) ppm.                29.sup.1                                                                            1 #STR123##                                                                               8 #STR124##                                                                              8 #STR125##   -- 514 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3                                                       ): δ =                                                                  1.4-1.8(m,4H),                                                                1.8-2.2(m,6H),                                                                2.4-2.5(m,1H), 3.0-3.1                                                        (m,2H),                                                                       3.2-3.6(m,10H),                                                               4.35(d,1H),                                                                   4.85(d,1H),                                                                   6.7-6.8(m,1H),                                                                7.05(m,1H), 7.2-7.4                                                           (m,6H) ppm.                30.sup.1                                                                            1 #STR126##                                                                               8 #STR127##                                                                              9 #STR128##   -- 542 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3                                                       ): δ =                                                                  1.05-1.45(m,4H),                                                              1.5-1.8(m,6H),                                                                1.85-2.2(m,6H),                                                               2.4-2.5(m,1H),                                                                2.95-3.4(m,6H),                                                               3.5-3.75(m,3H),                                                               4.35(d,1H),                                                                   4.85(d,1H),                                                                   5.7(br.d,1H),                                                                 6.8(m,1H), 7.05(d,1H),                                                        7.25-7.4 (m,6H) ppm.       31.sup.1                                                                            1 #STR129##                                                                               8 #STR130##                                                                              0 #STR131##   -- 528 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3                                                       ): δ =                                                                  1.45-1.8(m,8H),                                                               1.9-2.2(m,5H),                                                                2.4-2.5(m,1H),                                                                3.0-3.6(m,11H),                                                               4.35(d,1H), 4.9(d,1H),                                                        6.75(m,1H),                                                                   7.05(d,1H),                                                                   7.2-7.4(m,6H) ppm.         32.sup.1,5,9,10,17                                                                  2 #STR132##                                                                               8 #STR133##                                                                              4 #STR134##   -- 544 (m).sup.+                                                                      .sup.1 H-NMR(CDCl.sub.3                                                       ): δ =                                                                  0.25-0.4(m,2H),                                                               0.5-0.7(m,2H),                                                                1.0-1.1(m,1H),                                                                1.6-1.9(m,2H),                                                                1.95-2.2(m,5H),                                                               2.3-2.4(m,5H),                                                                2.7-2.8(m,2H),                                                                2.9-3.0(m,1H),                                                                3.15-3.2(m,5H),                                                               3.3-3.5(m,4H),                                                                3.8(d,1H), 4.3(s, 2H),                                                        7.1-7.15(m,1H),                                                               7.4-7.45(m,2H) ppm.                                                           Found: C, 49.17; H,                                                           6.04; N, 11.17.                                                               C.sub.24 H.sub.35                                                             N.sub.5 O.sub.3                                                               SCl.sub.2.                                                                    0.75CH.sub.2 Cl.sub.2                                                         requires: C, 48.87; H,                                                        6.05; N, 11.52%            33.sup.1,5,6                                                                        2 #STR135##                                                                               8 #STR136##                                                                              2 #STR137##   -- 466 (m).sup.+                                                                      Found: C, 57.84; H,                                                           6.47; N, 7.99.                                                                C.sub.24 H.sub.33                                                             N.sub.3 Cl.sub.2                                                              O.sub.2. 0.5CH.sub.2                                                          Cl.sub.2  requires C,                                                         57.82; H, 6.73; N,                                                            8.25%.                                                                        .sup.1 H-NMR(CDCl.sub.3                                                       ): δ =                                                                  0.2-0.4(m,2H),                                                                0.5-0.7(m,2H),                                                                1.0-1.15(m,1H),                                                               1.6-1.8(m,1H),                                                                1.8-1.95(m,1H),                                                               1.95-2.4(m,10H),                                                              2.75-2.9(m,2H),                                                               2.9-3.1(m,1H),                                                                3.2-3.25(m,1H),                                                               3.4-3.55(m,4H),                                                               3.6-3.8(m,5H),                                                                7.15(d,1H), 7.4(m,2H)                                                         ppm.                       34.sup.1,5,7                                                                        3 #STR138##                                                                               8 #STR139##                                                                              2 #STR140##   -- 508 (m).sup.+                                                                      Found: C, 62.57; H,                                                           7.55; N, 8.53.                                                                C.sub.27 H.sub.39                                                             Cl.sub.2 N.sub.3                                                              O.sub.2. CH.sub.2                                                             Cl.sub.2 requires C,                                                          62.96; H, 7.64; N,                                                            8.13%. .sup.1 H-NMR                                                           (CDCl.sub.3): δ                                                         = 0.9-1.1 (m,2H),                                                             1.1-1.3(m,3H),                                                                1.5-2.9(m,9H),                                                                1.9-2.4(m,10H),                                                               2.6-2.8(m,2H),                                                                2.85-3.0(m,1H),                                                               3.1-3.2(m,1H),                                                                3.3-3.6(m,4H), 3.6-                                                           3.8(m,4H), 7.1(d,1H),                                                         7.3(d,1H), 7.4(d,1H)                                                          ppm.                       35.sup.1,5,8                                                                        1 #STR141##                                                                               8 #STR142##                                                                              2 #STR143##   -- --   Found: C, 63.67; H,                                                           6.90; N, 8.35.                                                                C.sub.27 H.sub.33                                                             Cl.sub.2 N.sub.3                                                              O.sub.2.0.5H.sub.2 O                                                          requires C, 63.38; H,                                                         6.70; N, 8.21%. .sup.1                                                        H-NMR(CDCl.sub.3):                                                            δ = 1.6-1.8                                                             (m,1H),                                                                       1.95-2.3(m,10H),                                                              2.35-2.5 (m,1H),                                                              2.6-2.7(m,2H),                                                                2.8-2.95 (m,1H),                                                              3.2-3.35(m,3H),                                                               3.45-3.6 (m,1H),                                                              3.6-3.7(m,4H),                                                                4.4(d,1H), 4.8(d,1H),                                                         6.8(d,1H), 7.2-7.4                                                            (m,7H) ppm.                36.sup.1,5,7                                                                        4 #STR144##                                                                               8 #STR145##                                                                              2 #STR146##   -- 544 (m + 1).sup.+                                                                  Found: C, 57.30; H,                                                           6.66; N, 7.09.                                                                C.sub.27 H.sub.37                                                             Cl.sub.2 F.sub.2                                                              N.sub.3 O.sub.2.                                                              0.33CH.sub.2 Cl.sub.2                                                         requires: C, 57.33; H,                                                        6.65; N, 7.37%.                                                               .sup.1 H-NMR                                                                  (CDCl.sub.3): δ                                                         = 1.2-1.9 (m,9H),                                                             1.9-2.35(m,11H),                                                              2.35-2.5(m,1H),                                                               2.7-2.8(m,2H),                                                                2.85-3.0(m,1H),                                                               3.2-3.3(m,1H),                                                                3.3-3.45(m,4H),                                                               3.5-3.6(m,1H), 3.6-3.7                                                        (m,4H),                                                                       7.0-7.05(m,1H),                                                               7.3-7.35(m,1H),                                                               7.4(d,1H) ppm.             37.sup.1,5,7,13                                                                     2 #STR147##                                                                               8 #STR148##                                                                              3 #STR149##   -- --   Found: C, 60.74; H,                                                           7.29; N, 7.58.                                                                C.sub.27 H.sub.39                                                             N.sub.3 Cl.sub.2                                                              O.sub.2. 0.375CH.sub.2                                                        Cl.sub.2 requires: C,                                                         60.84; H, 7.42; N,                                                            7.78%. .sup.1 H-NMR                                                           (CDCl.sub.3): δ                                                         = 0.2-0.4 (m,2H),                                                             0.5-0.7(m,2H),                                                                0.95-1.1(m,1H), 1.1(t,                                                        3H), 1.45-1.7 (m,4H),                                                         1.7-2.3(m,12H),                                                               2.3-2.4(m,1H),                                                                2.45-2.6(m,2H), 2.6-                                                          2.8(m,2H),                                                                    2.8-2.95(m,1H),                                                               3.1-3.5(m,5H),                                                                3.7-3.8(m,1H),                                                                7.1(d,1H), 7.4(m,2H)                                                          ppm.                       38.sup.1,5,11,13,14                                                                 H                                                                                         8 #STR150##                                                                              4 #STR151##   -- 490 (m).sup.+                                                                      .sup.1 H-NMR(d.sub.6                                                          -DMSO/CDCl.sub.3):                                                            δ =1.5-1.7(m,1H),                                                        1.75-1.8(m,1H),                                                              1.9-2.2(m,5H),                                                                2.2-2.35(m,5H),                                                               2.6-2.65(m,2H),                                                               2.8-2.95(m,1H),                                                               3.0-3.2(m,4H),                                                                3.25-3.4(m,3H),                                                               3.65(d,1H), 5.25(s,                                                           2H), 6.2(s, 1H),                                                              7.05-7.1 (m,1H),                                                              7.3-7.4(m,2H) ppm.         39.sup.1,5,13                                                                       2 #STR152##                                                                               8 #STR153##                                                                              5 #STR154##   -- 614 (m + 1).sup.+                                                                  Found: C, 54.35; H,                                                           6.20; N, 10.87.                                                               C.sub.28 H.sub.41                                                             Cl.sub.2 N.sub.5                                                              O.sub.4 S. 0.25H.sub.2                                                        O requires: C, 54.31;                                                         H, 6.77; N, 11.31%.                                                           .sup.1 H-NMR                                                                  (CDCl.sub.3): δ                                                         = 0.2-0.35 (m,2H),                                                            0.5-0.7(m,2H),                                                                1.0-1.15(m,1H),                                                               1.7-1.9(m,1H),                                                                1.95-2.25(m,5H),                                                              2.3-2.45(m,5H),                                                               2.65-2.8(m,2H),                                                               2.95(t, 1H), 3.1-3.35                                                         (m,9H),                                                                       3.35-3.55(m,5H),                                                              3.65-3.8(m,5H),                                                               7.15-7.2(m,1H),                                                               7.4-7.45(m,2H) ppm.        40.sup.1,5,13                                                                       2 #STR155##                                                                               8 #STR156##                                                                              6 #STR157##   -- 558 (m + 1).sup.+                                                                  Found: C, 53.59; H,                                                           6.86; N, 12.11.                                                               C.sub.25 H.sub.37                                                             Cl.sub.2 N.sub.5                                                              O.sub.3 S requires: C,                                                        53.75; H, 6.69; N,                                                            12.54%. .sup.1                                                                H-NMR(CDCl.sub.3):                                                            δ = 0.25-0.4(m,2H                                                       ), 0.5-0.7(m,2H),                                                             1.0-1.1(m,1H),                                                                1.75-1.9(m,1H),                                                               1.9-2.3(m,4H),                                                                2.3-2.4(m,5H),                                                                2.6-2.7(d,6H),                                                                2.9-3.0(m,1H), 3.1-                                                           3.3(m,6H),                                                                    3.3-3.5(m,5H),                                                                3.8(d,1H), 7.15-7.2                                                           (m,1H), 7.4-7.45                                                              (m,2H) ppm.                41.sup.1,5,7,13                                                                     2 #STR158##                                                                               8 #STR159##                                                                              7 #STR160##   -- 572 (m + 1).sup.+                                                                  Found: C, 53.36; H,                                                           7.05; N, 11.63.                                                               C.sub.26 H.sub.39                                                             Cl.sub.2 N.sub.5                                                              O.sub.3 S. 0.5H.sub.2                                                         O requires: C, 53.69;                                                         H, 6.94; N, 12.04%.                                                           .sup.1 H-NMR(CDCl.sub.3                                                       ): δ = 0.2-0.4(m,                                                       2H), 0.5-0.7(m,2H),                                                           0.95-1.1(m,1H),                                                               1.7-1.9(m,1H),                                                                1.9-2.2(m,6H),                                                                2.2-2.45(m,5H),                                                               2.6-3.0(m,8H),                                                                3.1-3.55(m,10H),                                                              3.75(d,1H), 7.1(d,1H),                                                        7.35-7.4(m,2H) ppm.        42.sup.1,5,7,13                                                                     2 #STR161##                                                                               8 #STR162##                                                                              8 #STR163##   -- 481 (m + 1).sup.+                                                                  Found: C, 59.39; H,                                                           6.91; N, 8.16.                                                                C.sub.25 H.sub.35                                                             N.sub.3 O.sub.2                                                               Cl.sub.2. 0.4CH.sub.2                                                         Cl.sub.2 requires:  C,                                                        59.30; H, 7.01; N,                                                            8.17%. .sup.1 H-NMR                                                           (CDCl.sub.3): δ                                                         = 0.2-0.4 (m,2H),                                                             0.5-0.7(m,2H),                                                                0.95-1.1(m,1H),                                                               1.4-1.7(m,4H),                                                                1.7-2.2(m,10H),                                                               2.2-2.4(m,1H),                                                                2.45-2.6(m,2H),                                                               2.6-2.7(m,2H),  2.8-                                                          2.95(m,1H),                                                                   3.1-3.2(m,1H),                                                                3.35-3.5(m,4H),                                                               3.6-3.8(m,2H),                                                                7.1(d,1H), 7.35-7.4                                                           (m,2H) ppm.                43.sup.1,5,7,13                                                                     2 #STR164##                                                                               8 #STR165##                                                                              9 #STR166##   -- 543 (m).sup.+                                                                      .sup.1 H-NMR(CDCl.sub.3                                                       ): δ =                                                                  0.2-0.4(m,2H),                                                                0.5-0.65(m,2H),                                                               0.95-1.1(m,1H),                                                               1.65-1.9(m,3H),                                                               1.95-2.25(m,4H),                                                              2.3-2.45(m,5H),                                                               2.6-2.8(m,5H),                                                                2.9-3.0(m,1H),                                                                3.05-3.3(m,5H),                                                               3.3-3.5(m,4H),                                                                3.75(d,1H), 7.1(d,1H),                                                         7.35-7.4(m,2H)  ppm.      44.sup.1,5,7,15                                                                     5 #STR167##                                                                               8 #STR168##                                                                              0 #STR169##   -- 480 (m).sup.+                                                                      .sup.1 H-NMR(CDCl.sub.3                                                       ): δ =                                                                  0.0-0.2(m,2H),                                                                0.4-0.5(m,2H),                                                                0.6-0.75(m,1H),                                                               1.45(q, 2H), 1.55-1.7                                                         (m,1H),                                                                       1.75-1.9(m,1H),                                                               1.9-2.4(m,10H),                                                               2.65-2.8(m,2H),                                                               2.85-3.0(m,1H),                                                               3.2-3.45(m,4H),                                                               3.45-3.8(m,6H),                                                               7.05(d,1H), 7.2(d,1H),                                                        7.4(d,1H) ppm.             45.sup.1,5,7,13                                                                     5 #STR170##                                                                               8 #STR171##                                                                              1 #STR172##   -- 560 (m + 1).sup.+                                                                  Found: C, 54.63; H,                                                           6.83; N,  9.99.                                                               C.sub.28 H.sub.38                                                             N.sub.4 O.sub.3                                                               Cl.sub.2 S.                                                                   0.25CH.sub.2 Cl.sub.2                                                         requires:  C, 54.57;                                                          H, 6.72; N, 9.70%.                                                            .sup.1 H-NMR                                                                  (CDCl.sub.3): δ                                                         = 0.0-0.15 (m,2H),                                                            0.4-0.5(m,2H),                                                                0.6-0.75(m,1H),                                                               1.45(q, 2H), 1.5-1.65                                                         (m,1H), 1.7-1.9(m,1H),                                                         1.9-2.2(m,5H),                                                               2.3-2.45(m,5H),                                                               2.6-2.8(m,5H),                                                                2.95(t, 1H), 3.15-3.4                                                         (m,8H), 3.5-3.7(m,2H),                                                         7.05 (d,1H),                                                                 7.15(d,1H),  7.4(d,1H)                                                        ppm.                       46.sup.1,5,7,13                                                                     5 #STR173##                                                                               8 #STR174##                                                                              2 #STR175##   -- 593 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3                                                       ): δ =                                                                  0.0-0.15(m,2H),                                                               0.4-0.5(m,2H),                                                                0.6-0.75(m,1H),                                                               1.3-1.5(m,9H),                                                                1.5-2.2(m,12H),                                                               2.25-2.4(m,1H),                                                               2.5-2.7(m,3H),                                                                2.8-2.9(m,1H),                                                                3.2-3.5(m,9H),                                                                3.5-3.7(m,2H),                                                                4.4(br.s, 1H),                                                                7.05(d,1H),                                                                   7.2(d,1H), 7.4(d,1H)                                                          ppm.                       47.sup.1,5,7,13                                                                     5 #STR176##                                                                               8 #STR177##                                                                              3 #STR178##   -- 494 (m).sup.+                                                                      Found: C, 61.02; H,                                                           7.45; N,  8.47.                                                               C.sub.26 H.sub.37                                                             N.sub.3 O.sub.2                                                               Cl.sub.2. 0.25CH.sub.2                                                        Cl.sub.2 requires:  C,                                                        61.12; H, 7.34; N,                                                            8.15%. .sup.1 H-NMR                                                           (CDCl.sub.3): δ                                                         = 0.0-0.15 (m,2H),                                                            0.4-0.55 (m,2H),                                                              0.6-0.75 (m,1H),                                                              1.4-1.7 (m,5H),                                                               1.7-2.2 (m,11H),                                                              2.2-2.4 (m,1H),                                                               2.5-2.6 (m,2H),                                                               2.6-2.8 (m,2H),                                                               2.95(t, 1H),                                                                  3.2-3.5(m,4H),                                                                3.5-3.8(m,3H),                                                                7.05(d,1H),                                                                   7.25(d,1H),  7.4(d,1H)                                                        ppm.                       48.sup.1,5,7,13                                                                     2 #STR179##                                                                               8 #STR180##                                                                              4 #STR181##   -- 579 (m).sup.+                                                                      .sup.1 H-NMR(CDCl.sub.3                                                       ): δ =                                                                  0.2-0.4(m,2H),                                                                0.5-0.7(m,2H),                                                                0.95-1.1(m,1H),                                                               1.3-1.4(m,10H),                                                               1.55-1.65(m,1H),                                                              1.7-1.9(m,5H),                                                                1.9-2.4(m,6H),                                                                2.5-2.7(m,6H),                                                                2.95(t, 1H), 3.1-3.2                                                          (m,1H), 3.35-3.5                                                              (m,4H), 3.75(d,1H),                                                           4.4(br.s,1H),                                                                 7.1(d,1H),  7.4(m,2H)                                                         ppm.                       49.sup.1,5,7,13                                                                     6 #STR182##                                                                               8 #STR183##                                                                              5 #STR184##   -- 597 (m).sup.+                                                                      Found: C, 56.98; H,                                                           6.99; N,  9.25.                                                               C.sub.29 H.sub.42                                                             N.sub.4 Cl.sub.2                                                              O.sub.3 S.                                                                    0.25CH.sub.2 Cl.sub.2                                                         requires:  C, 56.76;                                                          H, 6.92; N, 9.05%.                                                            .sup.1 H-NMR                                                                  (CDCl.sub.3): δ                                                         = 0.05-0.25 (m,4H),                                                           0.4-0.55 (m,4H),                                                              0.56-0.7 (m,3H),                                                              1.5-1.7 (m,1H),                                                               1.75-1.9 (m,1H),                                                              1.9-2.25 (m,5H),                                                              2.3-2.45 (m,5H),                                                              2.6-2.8 (m,5H),                                                               2.95(t, 1H),                                                                  3.1-3.3(m,5H),                                                                3.3-3.4(m,2H), 3.5(q,                                                         2H), 3.8-3.9 (m,1H),                                                          7.05(d,1H),                                                                   7.3(d,1H), 7.4(d,1H)                                                          ppm.                       50.sup.1,5,7,15                                                                     ge,0006                                                                                   8 #STR185##                                                                              6 #STR186##   -- 520 (m).sup.+                                                                      Found: C, 62.67; H,                                                           6.88; N,  7.10.                                                               C.sub.28 H.sub.39                                                             N.sub.3 Cl.sub.2                                                              O.sub.2. 0.25CH.sub.2                                                         Cl.sub.2 requires: C,                                                         62.63; H, 7.35; N,                                                            7.76%. .sup.1 H-NMR                                                           (CDCl.sub.3): δ                                                         = 0.5-2.05 (m,4H),                                                            0.3-0.55 (m,4H),                                                              0.55-0.7 (m,3H),                                                              1.5-1.7 (m,1H), 1.8-                                                          1.95(m,1H), 1.95-2.4                                                          (m,10H), 2.6-2.8                                                              (m,2H), 2.8-2.9                                                               (m,1H), 3.1-3.2                                                               (m,1H), 3.3-3.45                                                              (m,2H), 3.5(q, 2H),                                                           3.6-3.7(m,4H),                                                                3.85-4.0(m,1H),                                                               7.05(m,1H), 7.3(m,1H),                                                        7.4(m,1H) ppm.             51.sup.1,5,13,16                                                                    6 #STR187##                                                                               8 #STR188##                                                                              7 #STR189##   -- 633 (m).sup.+                                                                      Found: C, 63.44; H,                                                           7.69; N,  8.34.                                                               C.sub.34 H.sub.50                                                             N.sub.4 Cl.sub.2                                                              O.sub.3. 0.125CH.sub.2                                                        Cl.sub.2 requires:  C,                                                        63.61; H, 7.86; N,                                                            8.70%. .sup.1 H-NMR                                                           (CDCl.sub.3): δ                                                         = 0.0-2.1 (m,4H),                                                             0.3-0.7 (m,7H),                                                               1.2-2.2 (m,23H),                                                              2.3-2.45 (m,1H),                                                              2.5-2.7 (m,4H),                                                               2.8-2.9 (m,1H),                                                               3.1-3.2 (m,1H),                                                               3.3-3.6 (m,4H),                                                               3.8-3.95 (m,1H),                                                              4.4(br.s,1H),                                                                 7.05(d,1H), 7.3(d,1H),                                                         7.4(d,1H) ppm.            52.sup.1,5,13,16                                                                    6 #STR190##                                                                               8 #STR191##                                                                              8 #STR192##   -- 534 (m).sup.+                                                                      Found: C, 63.34; H,                                                           7.86; N,  7.36.                                                               C.sub.29 H.sub.41                                                             N.sub.3 Cl.sub.2                                                              O.sub.2.0.25 CH.sub.2                                                         Cl.sub.2 requires: C,                                                         63.21; N,  7.53; N,                                                           7.56%.                                                                        .sup.1 H-NMR(CDCl.sub.3                                                       ):  δ = 0.25-0.50                                                       (m,4H),                                                                       0.35-0.55(m,4H),                                                              0.55-0.75(m,3H),                                                              1.2-1.75(m,3H),                                                               1.8-2.2(m,11H),                                                               2.3-2.4(m,1H),  2.4-                                                          2.8(m,4H),                                                                    2.8-2.9(m,1H),                                                                3.1-3.2(m,1H),                                                                3.4-3.6(m,4H),                                                                3.6-3.8(m,1H),                                                                3.8-4.0(m,1H),                                                                7.05(d,1H),                                                                   7.25(d,1H),  7.4(d,1H)                                                        ppm.                       53.sup.1,5,13,16                                                                    6 #STR193##                                                                               8 #STR194##                                                                              9 #STR195##   -- 598 (m).sup.+                                                                      Found: C, 52.55; H,                                                           7.00; N, 9.39.                                                                C.sub.28 H.sub.41                                                             N.sub.5 Cl.sub.2                                                              O.sub.3 S.0.75CH.sub.2                                                        Cl.sub.2 requires: C,                                                         52.13; H, 6.47; N,                                                            10.50%. .sup.1                                                                H-NMR(CDCl.sub.3):                                                            δ = 0.0-0.3                                                             (m,4H), 0.3-0.5(m,4H),                                                        0.5-0.7 (m,3H),                                                               1.5-1.6(m,1H), 1.7-1.8                                                        (m,1H), 1.9-2.2(m,5H),                                                        2.3-2.4 (m,5H),                                                               2.6-2.8(m,2H), 2.9(t,                                                         1H), 3.1-3.2(m,4H),                                                           3.3-3.4(m,2H), 3.5(q,                                                         2H), 3.85-3.95(m,2H),                                                         4.25(s, 2H),                                                                  7.05(d,1H), 7.25                                                              (d,1H), 7.4(d,1H)                                                             ppm.                       54.sup.1,5,13                                                                       4 #STR196##                                                                               8 #STR197##                                                                              0 #STR198##   -- 657 (m).sup.+                                                                      Found: C, 53.85; H,                                                           6.78; N,  7.42.                                                               C.sub.33 H.sub.46                                                             N.sub.4 Cl.sub.2                                                              O.sub.3 F.sub.2.0.2                                                           CH.sub.2 Cl.sub.2                                                             requires: C, 54.08; H,                                                         6.69; N, 7.38%.                                                              .sup.1 H-NMR(CDCl.sub.3                                                       ):  δ = 1.25-1.5(                                                       m,13H),                                                                       1.5-1.95(m,11H),                                                              1.9-2.2(m,7H),                                                                2.3-2.4(m,1H),                                                                2.5-2.7(m,4H),                                                                2.85(t, 1H), 3.1- 3.3                                                         (m,1H), 3.3-3.6(m,6H),                                                         4.4(br.s,1H),                                                                7.05(d,1H),                                                                   7.2(d,1H), 7.4(d,1H)                                                          ppm.                       55.sup.1,5,7,13                                                                     4 #STR199##                                                                               8 #STR200##                                                                              1 #STR201##   -- 558 (m).sup.+                                                                      Found: C, 57.74; H,                                                           6.73; N,  7.01.                                                               C.sub.28 H.sub.39                                                             N.sub.3 Cl.sub.2                                                              O.sub.2 F.sub.2.                                                              0.4CH.sub.2 Cl.sub.2                                                          requires: C,  57.57;                                                          H, 6.77; N, 7.09%.                                                            .sup.1 H-NMR                                                                  (CDCl.sub.3): δ                                                         = 1.2-1.4 (m,2H),                                                             1.4-2.3 (m,20H),                                                              2.3-2.45 (m,2H),                                                              2.5-2.6 (m,2H),                                                               2.6-2.75 (m,2H),                                                              2.9(t, 1H),                                                                   3.15-3.2(m,1H),                                                               3.3-3.5(m,4H),                                                                3.6-3.8(m,2H),                                                                7.05(d,1H), 7.3(d,1H),                                                         7.4(d,1H) ppm.            56.sup.1,5,7,13                                                                     4 #STR202##                                                                               8 #STR203##                                                                              2 #STR204##   -- --   .sup.1 H-NMR(CDCl.sub.3                                                       ): δ =                                                                  1.25-1.5(m,2H),                                                               1.5-1.9(m,8H),                                                                1.9-2.3(m,7H),                                                                2.3-2.4(m,4H),                                                                2.6-2.8(m,5H),                                                                2.95(t, 1H), 3.15-3.2                                                         (m,5H), 3.3-3.4                                                               (m,4H), 3.4(d,1H),                                                            7.05 (d,1H),                                                                  7.25(d,1H), 7.4 (d,1H)                                                        ppm.                       57.sup.1,5,7,13                                                                     7 #STR205##                                                                               8 #STR206##                                                                              3 #STR207##   -- 660 (m).sup.+                                                                      Found: C, 53.58; H,                                                           7.11; N,  10.43.                                                              C.sub.30 H.sub.47                                                             Cl.sub.2 SN.sub.5                                                             O.sub.5. 0.5H.sub.2 O                                                         requires: C, 53.76; H,                                                        7.24; N,  10.45%.                                                             .sup.1 H-NMR(CDCl.sub.3                                                       ): δ =1.2-1.4(m,2                                                       H),  1.4(s, 9H),                                                              1.4-1.7 (m,6H),                                                               1.7-1.9 (m,1H),                                                               1.9-2.25 (m,8H),                                                              2.3-2.45 (m,4H),                                                              2.7(q, 2H),                                                                   2.9-3.0(m,1H),                                                                3.1-3.3(m,4H),                                                                3.3-3.4(m,3H),                                                                3.4-3.6(m,2H),  4.3(s,                                                        2H), 7.05(d,1H),                                                              7.2(d,1H), 7.4(d,1H)                                                          ppm.                       58.sup.1,7,12,13                                                                    2 #STR208##                                                                               8 #STR209##                                                                              3 #STR210##   -- --   .sup.1 H-NMR(CDCl.sub.3                                                       ): δ =                                                                  0.25-0.4(m,2H),                                                               0.5-0.7(m,2H),                                                                1.0-1.1(m,1H),                                                                1.6-1.9(m,2H),                                                                1.95-2.2(m,5H),                                                               2.3-2.4(m,5H),                                                                2.7-2.8(m,2H),                                                                2.9-3.0(m,1H),                                                                3.15-3.2(m,5H),                                                               3.3-3.5(m,4H),                                                                3.8(d,1H), 4.3(s, 2H),                                                         7.1-7.15(m,1H),                                                              7.4-7.45(m,2H)  ppm.       59.sup.1,5,7                                                                        2 #STR211##                                                                               8 #STR212##                                                                              4 #STR213##   -- 522 (m).sup.+                                                                      Found: C, 59.47; H,                                                           7.33; N,  7.66.                                                               C.sub.27 H.sub.37                                                             Cl.sub.2 N.sub.3                                                              O.sub.3. 0.35CH.sub.2                                                         Cl.sub.2 requires:  C,                                                        59.49; H, 6.88; N,                                                            7.61%.                                                                        .sup.1 H-NMR(CDCl.sub.3                                                       ):  δ = 0.2-0.4(m                                                       ,2H),  0.5-0.77(m,2H),                                                         0.9-1.1(m,1H),                                                               1.6-2.4(m,15H),                                                               2.5-2.7(m,2H),                                                                2.7-2.8(m,2H),                                                                2.85-3.0(m,1H),                                                               3.1-3.2(m,1H),                                                                3.3-3.6(m,4H),                                                                3.65(s, 3H),                                                                  3.8(d,1H),                                                                    7.05(d,1H), 7.3-7.5                                                           (m,2H)                     __________________________________________________________________________                                                       ppm.                        Footnotes                                                                     .sup.1. At least 2 mol. equiv. of triethylamine used.                         .sup.2. See Example 103 for an alternative preparation.                       .sup.3. Dichloromethane additionally used as a cosolvent for the reaction     .sup.4. 3 (1HImidazol-1-yl)azetidine dihydrochloride used as the starting     material was prepared by treatment of                                         1(t-butoxycarbonyl)-3-(1H-imidazol-1-yl)azetidine with hydrogen chloride      in dichloromethane by the method described in International Patent            Publication No. WO93/19059.                                                   .sup.5. (S) enantiomer prepared.                                              .sup.6. Additional quantities of the azetidine starting material(ca. 1        mol. equiv.) triethylamine(ca. 2 mol. equiv.) and tetrahydrofuran,            followed by sodium triacetoxyborohydride(ca. 1.5 mol. equiv.) and glacial     acetic acid, were added later to drive the reaction towards completion.       Methanol/dichloromethane was used as the column eluant.                       .sup.7. A gradient elution was performed using dichloromethane followed b     dichloromethane/methanol as the column eluant.                                .sup.8. A gradient elution was initially performed using ethyl acetate        followed by ethyl acetate/methanol as the column eluant and this was then     changed to dichloromethane/methanol in the later stages.                      .sup.9. 3 (4Aminosulphonylpiperazin-1-yl)azetidine bistrifluoroacetate(se     Preparation 154) was used as the starting material.                           .sup.10. The crude reaction product was purified as the trifluoroacetate      salt by chromatography on silica gel eluting with dichloromethane:            methanol: 0.880 aqueous ammonia solution(89:10:1, by volume). The purifie     salt was treated with 10% aqueous potassium carbonate solution and the        aqueous layer extracted several times with ethyl acetate. The combined        organic extracts were dried(Na.sub.2 SO.sub.4) and concentrated under         reduced pressure to give the required product.                                .sup.11. Purified by reverse phase chromatography using MCI gel(trade         mark)(a high porous polystyrene polymer CHP 20P [75150 μ] using            methanol followed by methanol:water as the eluant.                            .sup.12. (R) enantiomer prepared.                                             .sup.13. The ditrifluoroacetate salt of the azetidine starting material       was used.                                                                     .sup.14. Reference Example only.                                              .sup.15. The dihydrochloride salt of the azetidine starting material was      used.                                                                         .sup.16. A gradient elution was performed using dichloromethane:methanol      followed by dichloromethane:methanol:concentrated aqueous ammonia solutio     as the eluant.                                                                .sup.17. [α].sub.D.sup.25 + 48.9° (c = 0.0009 in methanol)  

EXAMPLE 605-(3,4-Dichlorophenyl)-1-(3-methoxybenzyl)-5-(2-[3-morpholinoazetidin-1-yl]ethyl)-2-piperidone##STR214## To a solution of the piperidone (see Example 1) (350 mg, 0.85mmol) in dry N,N-dimethylformamide (5 ml) under nitrogen was added 60%w/w sodium hydride dispersion in oil (37 mg, 1.05 mol. equiv.) and themixture was stirred at room temperature for thirty minutes. After thistime, 3-methoxybenzyl chloride (0.13 ml, 1.05 mol. equiv.) was added andthe mixture was stirred for five minutes. Water (1 ml) was then addedfollowed by saturated aqueous sodium bicarbonate solution (20 ml) andsaturated aqueous ammonium chloride solution (20 ml). The mixture wasextracted with ethyl acetate (2×20 ml) and the combined organic layerswashed with saturated aqueous ammonium chloride solution (2×20 ml) andthen dried over magnesium sulphate. Filtration and removal of thesolvent from the filtrate under reduced pressure gave a gum which waschromatographed on silica gel eluting with a solvent gradient ofmethanol:dichloromethane (1:19 to 1:9, by volume) to give the titlecompound (140 mg). TLC R_(f) =0.45 (silica, methanol:dichloromethane,1:9, by volume). LRMS m/z=532(m)⁺. Found: C, 62.07; H, 6.74; N, 7.19.C₂₈ H₃₅ Cl₂ N₃ O₃. 0.1 CH₂ Cl₂ requires C, 62.39; H, 6.56; N, 7.77%.

¹ H-NMR (CDCl₃):δ=1.50-2.90 (m,16H), 3.25-3.80 (m,7H), 3.80 (s,3H), 4.30(d,1H), 4.80 (d,1H), 6.80-6.90 (m,4H), 7.05 (d,1H), 7.25-7.30 (m,2H)ppm.

EXAMPLES 61 to 75

The compounds of the following tabulated Examples of the generalformula: ##STR215## were prepared by a similar method to that of Example60 (with heating of the reaction mixture, H necessary) using theappropriate piperidone (see Example 1) and chloro, bromo ormethanesulphonyloxyalkane derivatives as the starting materials.

    __________________________________________________________________________    Ex                                      LRMS                                  No. R           R.sup.1                                                       x.sup.1 -R.sup.2                                                                  m.p.        m/z       Analysis/.sup.1 H-NMR                               __________________________________________________________________________    61.sup.3                                                                          1 #STR216##                                                                               6 #STR217##                                                                             7 #STR218##                                                                            --   609 (m + 1).sup.+                                                                  Found: C, 56.15; H, 6.17; N,                                                  8.45. C.sub.29 H.sub.38                                                       Cl.sub.2 N.sub.4 O.sub.4                                                      S.0.15CH.sub.2 Cl.sub.2                                                       requires C, 56.26; H, 6.20;                                                   N, 9.00%. .sup.1 H-NMR(CDCl.s                                                 ub.3): δ = 1.4-1.8 (m,                                                  3H), 1.95-2.4(m, 9H),                                                         2.4-2.6 (m, 1H), 2.6-3.0(m,                                                   8H), 3.25 - 3.4(m, 3H),                                                       3.6-3.80(m, 5H), 4.55(d,                                                      1H), 4.8(d, 1H), 6.9-                                                         6.95(m, 1H), 7.1(d, 1H),                                                      7.25-7.4(m, 1H), 7.5-7.55(m,                                                  2H), 7-7.8(m, 2H) ppm.           62.sup.3                                                                          2 #STR219##                                                                               6 #STR220##                                                                             7 #STR221##                                                                            --   516 (m).sup.+                                                                      .sup.1 H-NMR(CDCl.sub.3):                                                     δ = 1.5-1.8 (m, 3H),                                                    1.95-2.55(m, 12H), 2.6-                                                       2.75(m, 2H), 2.8-2.95(m,                                                      1H), 3.2- 3.35(m, 3H),                                                        3.55-3.75(m, 5H), 4.35(d,                                                     1H), 4.8(d, 1H), 6.8-6.85                                                     (m, 1H), 7.05-7.3(m, 6H)                                                      ppm.                             63.sup.3                                                                          3 #STR222##                                                                               6 #STR223##                                                                             7 #STR224##                                                                            56- 62° C.                                                                  508 (m + 1).sup.+                                                                  Found: C, 62.87; H, 7.59; N,                                                  7.95. C.sub.27 H.sub.39                                                       Cl.sub.2 N.sub.3 O.sub.2.0.1C                                                 H.sub.2 Cl.sub.2 requires C,                                                  62.96; H, 7.64; N, 8.13%.                                                     .sup.1 H-NMR(CDCl.sub.3):                                                     δ = 0.9-1.1 (m, 2H),                                                    1.15-1.35(m, 3H), 1.45-                                                       1.85(m, 8H), 1.95-2.4(m,                                                      10H), 2.7-2.8(m, 2H),                                                         2.85-2.95(m, 1H),                                                             3.10-3.2(m, 1H), 3.3-3.4(m,                                                   4H), 3.55(d, 1H),                                                             3.65-3.75(m, 4H),                                                             7.05-7.1(m, 1H),                                                              7.25-7.35(m, 1H),                                                             7.35-7.4(m, 1H) ppm.             64.sup.3                                                                          4 #STR225##                                                                               6 #STR226##                                                                             7 #STR227##                                                                            --   544 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3):                                                     δ =1.5-1.85 (m, 3H),                                                    1.95-2.3(m, 8H), 2.4-2.55                                                     (m, 1H), 2.6-2.7(m, 5H),                                                      2.7-2.95 (m, 1H),                                                             3.25-3.4(m, 3H), 3.5-3.7 (m,                                                  5H), 4.4(d, 1H), 4.9(d, 1H),                                                  6.8- 6.9(m, 1H), 7.0-7.05(m,                                                  1H), 7.3 (s, 1H),                                                             7.5-7.55(m, 2H), 7.9-7.95                                                     (m, 2H) ppm.                     65.sup.3                                                                          5 #STR228##                                                                               6 #STR229##                                                                             7 #STR230##                                                                            --   570 (m + 1).sup.+                                                                  Found: C, 58.09; H, 5.54; N,                                                  8.57. C.sub.28 H.sub.32                                                       Cl.sub.2 N.sub.3 O.sub.2                                                      F.sub.3.0.06CH.sub.2                                                          Cl.sub.2 requires C, 58.54;                                                   H, 5.62; N, 7.30%. .sup.1                                                     H-NMR(CDCl.sub.3): δ =                                                  1.5-1.8 (m, 3H),                                                              1.95-2.15(m, 3H), 2.2-2.4                                                     (m, 5H), 2.5-2.75(m, 3H),                                                     2.85-2.9 (m, 1H),                                                             3.3-3.35(m, 3H), 3.5-3.6 (m,                                                  1H), 3.65-3.7(m, 4H), 4.65                                                    (d, 1H), 5.0(d, 1H),                                                          6.9-7.75(m, 7H) ppm.             66.sup.2                                                                          6 #STR231##                                                                               6 #STR232##                                                                             7 #STR233##                                                                            --   503 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3):                                                     δ = 1.55-2.5 (m, 12H),                                                  2.65-2.8(m, 2H), 2.8-3.0 (m,                                                  1H), 3.3-3.5(m, 3H),                                                          3.65-3.9 (m, 5H), 4.5(d,                                                      1H), 4.9(d, 1H), 6.9- 7.0(m,                                                  1H), 7.15-7.4(m, 4H), 7.6-                                                    7.7(m, 1H), 8.6-8.8(m, 1H)                                                    ppm.                             67.sup.2                                                                          7 #STR234##                                                                               6 #STR235##                                                                             7 #STR236##                                                                            --   503 (m + 1).sup.+                                                                  Found: C, 60.96; H, 6.25; N,                                                  10.88. C.sub.26 H.sub.32                                                      Cl.sub.2 N.sub.4 O.sub.2.0.15                                                 CH.sub.2 Cl.sub.2 requires                                                    C, 60.84; H, 6.31; N,                                                         10.85%. .sup.1 H-NMR(CDCl.sub                                                 .3): δ = 1.45-1.6 (m,                                                   1H), 1.6-1.8(m, 2H),                                                          1.95-2.1 (m, 3H), 2.1-2.3(m,                                                  5H), 2.4-2.5 (m, 1H),                                                         2.65-2.7(m, 2H), 2.8-2.9 (m,                                                  1H), 3.25-3.4(m, 3H),                                                         3.5-3.6 (m, 1H), 3.6-3.75(m,                                                  4H), 4.4 (d, 1H), 4.8(d,                                                      1H), 6.8-6.9(d, 1H), 7.05(s,                                                  1H), 7.25-7.35(m, 2H), 7.6-                                                   7.7(d, 1H), 8.5-8.6(m, 2H)                                                    ppm.                             68.sup.2                                                                          8 #STR237##                                                                               6 #STR238##                                                                             7 #STR239##                                                                            52- 58° C.                                                                  503 (m + 1).sup.+                                                                  Found: C, 60.11; H, 6.49; N,                                                  10.72. C.sub.26 H.sub.32                                                      Cl.sub.2 N.sub.4 O.sub.2.0.15                                                  CH.sub.2 Cl.sub.2 requires                                                   C, 60.84; H, 6.31; N,                                                         10.85%. .sup.1 H-NMR(CDCl.sub                                                 .3): δ = 1.5-1.8 (m,                                                    3H), 1.95-2.4(m, 8H),                                                         2.4-2.55 (m, 1H),                                                             2.65-2.75(m, 2H), 2.8-2.9                                                     (m, 1H), 3.25-3.4(m, 3H),                                                     3.5-3.7 (m, 5H), 4.45(d,                                                      1H), 4.7(m, 1H), 6.9-6.95(m,                                                  1H), 7.1-7.35(m, 4H),                                                         8.6-8.65(m, 2H) ppm.             69.sup.3                                                                          9 #STR240##                                                                               6 #STR241##                                                                             7 #STR242##                                                                            --   468 (m + 1).sup.+                                                                  Found: C, 60.94; H, 7.15; N,                                                  9.99. C.sub.24 H.sub.33                                                       Cl.sub.2 N.sub.3 O.sub.2.0.08                                                 CH.sub.2 Cl.sub.2 requires                                                    C, 61.11; H, 7.06; N, 8,88%.                                                  .sup.1 H-NMR(CDCl.sub.3):                                                     δ = 0.25-0.4 (m, 2H),                                                   0.55-0.7(m, 2H), 1.0-1.15                                                     (m, 1H), 1.6-1.7(m, 1H),                                                      1.8-1.9 (m, 1H), 1.95-2.4                                                     (m, 10H), 2.7-2.8 (m, 2H),                                                    2.85-3.0(m, 1H), 3.15-3.2                                                     (m, 1H), 3.3-3.5(m, 4H),                                                      3.75-3.8 (m, 5H),                                                             7.15-7.45(m, 3H) ppm.            70.sup.4                                                                          0 #STR243##                                                                               6 #STR244##                                                                             7 #STR245##                                                                            --   480 (m + 1).sup.+                                                                  Found: C, 61.75; H, 7.63; N,                                                  8.77. C.sub.25 H.sub.35                                                       Cl.sub.2 N.sub.3 O.sub.2.0.05                                                 CH.sub.2 Cl.sub.2 requires                                                    C, 62.07; H, 7.30; N, 8.67%.                                                  .sup.1 H-NMR(CDCl.sub.3):                                                     δ = 1.55-2.4 (m, 18H),                                                  2.6-2.8(m, 3H), 2.85-2.95                                                     (m, 1H), 3.3-3.75(m, 10H),                                                    7.05- 7.45(m, 3H) ppm.           71.sup.4                                                                          1 #STR246##                                                                               6 #STR247##                                                                             7 #STR248##                                                                            --   494 (m + 1).sup.+                                                                  Found: C, 61.89; H, 7.45; N,                                                  8.11. C.sub.26 H.sub.37                                                       Cl.sub.2 N.sub.3 O.sub.2.0.05                                                 CH.sub.2 Cl.sub.2 requires                                                    C, 62.73; H, 7.50;  N,                                                        8.43%. .sup.1 H-NMR(CDCl.sub.                                                 3): δ = 1.15-1.3 (m,                                                    2H), 1.45-2.4(m, 19H),                                                        2.7-2.75 (m, 2H),                                                             2.85-2.95(m, 1H), 3.2-3.7                                                     (m, 10H), 7.1-7.4(m, 3H)                                                      ppm.                             72.sup.4                                                                          2 #STR249##                                                                               6 #STR250##                                                                             7 #STR251##                                                                            52- 60° C.                                                                  522 (m + 1).sup.+                                                                  Found: C, 63.50; H, 8.18; N,                                                  7.89. C.sub.28 H.sub.41                                                       Cl.sub.2 N.sub.3 O.sub.2.0.1C                                                 H.sub.2 Cl.sub.2 requires C,                                                  63.55; H, 7.82;  N, 7.91%.                                                    .sup.1 H-NMR(CDCl.sub.3):                                                     δ = 0.85-1.0 (m, 2H),                                                   1.1-1.3(m, 4H), 1.4-1.5 (m,                                                   2H), 1.55-1.85(m, 8H),                                                        1.95-2.4 (m, 9H),                                                             2.65-2.75(m, 2H), 2.85-                                                       2.95(m, 1H), 3.3-3.7(m,                                                       10H), 7.05-7.45(m, 3H) ppm.      73.sup.4                                                                          3 #STR252##                                                                               6 #STR253##                                                                             7 #STR254##                                                                            50- 61° C.                                                                  522 (m + 1).sup.+                                                                  Found: C, 64.71; H, 7.94; N,                                                  7.98. C.sub.28 H.sub.41                                                       Cl.sub.2 N.sub.3 O.sub.2.0.08                                                 CH.sub.2 Cl.sub.2 requires                                                    C, 63.71; H, 7.84;  N,                                                        7.94%. .sup.1 H-NMR(CDCl.sub.                                                 3): δ = 0.9-1.15 (m,                                                    4H), 1.15-1.4(m, 4H),                                                         1.4-1.55 (m, 2H),                                                             1.55-1.95(m, 6H), 1.95-2.3                                                    (m, 9H), 2.3-2.5(m, 1H),                                                      2.7-2.8 (m, 2H), 2.85-3.0(m,                                                  1H), 3.2-3.5 (m, 4H),                                                         3.5-3.6(m, 1H), 3.65-3.75                                                     (m, 4H), 7.05-7.1(m, 1H),                                                     7.3-7.35 (s, 1H),                                                             7.4-7.45(d, 1H) ppm.             74.sup.4                                                                          4 #STR255##                                                                               6 #STR256##                                                                             7 #STR257##                                                                            --   522 (m + 1).sup.+                                                                  Found: C, 62.37; H, 7.89; N,                                                  7.70. C.sub.28 H.sub.41                                                       Cl.sub.2 N.sub.3 O.sub.2.0.2                                                  CH.sub.2 Cl.sub.2 requires                                                    C, 62.77; H, 7.73;  N,                                                        7.79%. .sup.1 H-NMR                                                           (CDCl.sub.3): δ =                                                       0.8-1.5 (m, 10H),                                                             1.5-2.05(m, 7H), 2.05-2.2                                                     (m, 9H), 2.4-2.5(m, 1H),                                                      2.65-2.8 (m, 2H),                                                             2.85-3.1(m, 2H), 3.15-3.25                                                    (s, 1H), 3.3-3.5(m, 2H),                                                      3.8-3.95 (m, 4H), 7.1-7.2(m,                                                  1H), 7.3-7.45 (m, 2H) ppm.       75.sup.1,3                                                                        5 #STR258##                                                                               6 #STR259##                                                                             7 #STR260##                                                                            --   516 (m + 1).sup.+                                                                  Enantiomeric pair A .sup.1                                                    H-NMR(CDCl.sub.3): δ =                                                  1.2-1.4 (m, 1H), 1.5-1.65(m,                                                  3H), 1.75-2.15 (m, 4H),                                                       2.15-2.35(m, 4H), 2.35-2.4                                                    (m, 1H), 2.4-2.5(m, 1H),                                                      2.5-2.6 (m, 2H), 2.75-2.9(m,                                                  2H), 3.2-3.3 (m, 2H),                                                         3.3-3.4(d, 1H), 3.6-3.8 (m,                                                   4H), 6.15-6.25(m, 1H), 6.95-                                                  7.05(d, 1H), 7.25-7.5(m,                                                      8H), ppm.                                                                516  Enantiomeric pair B                                                      (m + 1).sup.+                                                                      Found: C, 61.84; H, 6.81; N,                                                  7.02.                                                                         C.sub.28 H.sub.35 Cl.sub.2                                                    N.sub.3 O.sub.2.0.3CH.sub.2                                                   Cl.sub.2                                                                      requires C, 62.71; H, 6.62;                                                   N,                                                                            7.75%.                                                                        .sup.1 H-NMR (CDCl.sub.3):                                                    δ = 1.2-1.4                                                             (m, 1H), 1.5-1.75(m, 4H),                                                     1.75-2.1                                                                      (m, 4H), 2.1-2.35(m, 6H),                                                     2.35-2.5                                                                      (m, 1H), 2.6-2.75(m, 2H),                                                     2.8-2.95                                                                      (m, 1H), 3.1-3.2(d, 1H),                                                      3.3-3.4                                                                       (m, 2H), 3.6-3.75(m, 4H),                                                     6.15-6.25                                                                     (m, 1H), 6.35-6.4(d, 1H),                                                     7.05-7.1                                                                      (d, 1H), 7.25-7.4(m, 6H)         __________________________________________________________________________                                                 ppm.                              Footnotes                                                                     .sup.1. The two pairs of enantiomers in the product obtained after the        workup were separated by chromatography on silica gel eluting with a          solvent gradient of methanol:dichloromethane (1:19 to 1:9). Enantiomeric      pair A eluted first followed by the more polar enantiomeric pair B.           .sup.2. Chloroalkane derivative used as the starting material.                .sup.3. Bromoalkane derivative used as the starting material.                 .sup.4. Methanesulphonyloxyalkane derivative used as the starting             material.                                                                

EXAMPLE 761-Cycloheptylmethyl-5-(3,4-dichlorophenyl)-5-(2-[3-morpholinoazetidin-1-yl]ethyl)-2-piperidone##STR261##

To a solution of the piperidone (see Example 1) (200 mg, 0.49 mmol) indry N,N-dimethylformamide (3.5 ml) at 0° C. under nitrogen was added 60%w/w sodium hydride dispersion in oil (21 mg, 1.1 mol. equiv.) and themixture was allowed to warm to room temperature over one hour. Afterthis time, a solution of methane-sulphonyloxymethylcycloheptane (seePreparation 13) (120 mg, 1.2 mol. equiv.) in dry N,N-dimethylformamide(0.5 ml) was added and the mixture was heated to 50° C. To effectcomplete reaction of the starting piperidone the mixture was cooled,further portions of sodium hydride (0.5 mol. equiv.) and the startingmesylate (0.5 mol. equiv.) were then added and the reaction was heatedto 50° C. for two hours. The reaction was cooled to 0° C., water (1 ml)added and the dimethylformamide removed under reduced pressure. Theresidue was extracted with ethyl acetate (3×20 ml), and the combinedextracts were dried over magnesium sulphate. Filtration and removal ofthe solvent from the filtrate under reduced pressure gave a foam whichwas chromatographed using silica gel eluting with a solvent gradient ofdichloromethane:methanol (100:0 to 85:15, by volume) to give the titlecompound (120 mg). TLC R_(f) =0.45 (silica, methanol:dichloromethane,1:9 by volume). LRMS m/z 522 (m+1)⁺. Found: C, 62.11; H, 7.63; N, 7.55.C₂₈ H₄₁ Cl₂ N₃ O₂.0.2 CH₂ Cl₂ requires C, 62.78; H, 7.73; N, 7.79%.

¹ H-NMR (CDCl₃):δ=1.1-1.3 (m,2H), 1.35-1.8 (m,11H), 1.8-1.95 (m,2H),1.95-2.1 (m,1H), 2.1-2.35 (m,7H), 2.35-2.5 (m,1H), 2.75-2.95 (m,2H),2.95-3.0 (m,2H), 3.05-3.2 (m,2H), 3.25-3.45 (m,2H), 3.45-3.6 (m,2H),3.6-3.75 (m,4H), 7.05-7.1 (m,1H), 7.3-7.35 (m,1H), 7.4-7.45 (m,1H) ppm.

EXAMPLE 775-(3,4-Dichlorophenyl)-5-(2-[3-morpholinoazetidin-1-yl]ethyl)-1-(4-phenylbenzyl)-2-piperidone##STR262##

To a solution of the mesylate (see Preparation 35) (290 mg, 0.55 mmol)in dry acetonitrile (10 ml) was added 3-morpholinoazetidinedihydrochloride (see Preparation 56) (200 mg, 2.0 mol. equiv.) followedby triethylamine (0.15 ml, 2 mol. equiv.) and potassium carbonate (150mg, 2 mol. equiv.). The mixture was heated under reflux for four hours.After this time, the reaction was cooled, water (1 ml) was added, themixture was evaporated to dryness under reduced pressure and the residuetaken up in a mixture of dichloromethane (10 ml) and water (10 ml). Theorganic phase was separated, washed with brine (10 ml), dried overmagnesium sulphate, filtered, and the solvent removed from the filtrateunder reduced pressure to give a gum which was chromatographed on silicagel eluting with a solvent gradient of methanol:dichloromethane (1:19 to1:9, by volume) to give the title compound (85 mg). TLC R_(f) =0.47(silica, methanol:dichloromethane, 1:9, by volume). m.p. 72-82° C. LRMSm/z=578 (m+1)⁺. Found: C, 67.56; H, 6.27; N, 7.24. C₃₃ H₃₇ Cl₂ N₃O₂.0.13 CH₂ Cl₂ requires C, 67.53; H, 6.37; N, 7.13%.

¹ H-NMR (CDCl₃):δ=1.5-1.8 (m,3H), 1.95-2.3 (m,8H), 2.4-2.55 (m,1H),2.6-2.75 (m,2H), 2.8-2.9 (m,1H), 3.3-3.35 (m,3H), 3.55-3.7 (m,5H), 4.4(d,1H), 4.9 (d,1H), 6.85-6.9 (m,1H), 7.1 (s,1H), 7.25-7.7 (m,10H) ppm.

EXAMPLES 78 to 96

The compounds of the following tabulated Examples of the generalformula: ##STR263## were prepared by a similar method to that of Example77 using the appropriate mesylate (see Preparations 33, 34, 36, 37 and38) and the appropriate azetidine (see Preparations 56, 68, 77, 81, 82,83, 86, 87, 88, 119, 134, 154, 179 and 181) starting materials.

    __________________________________________________________________________    Ex.                                   LRMS                                    No.                                                                              R         R.sup.1 --X.sup.1 --R.sup.2                                                                         m.p.                                                                             m/z  Analysis/.sup.1 H-NMR              __________________________________________________________________________    78                                                                               1 #STR264##                                                                             5 #STR265##                                                                           7 #STR266##   -- 515 (m).sup.+                                                                      Found: C, 64.60; H, 6.68; N,                                                  10.19. C.sub.28 H.sub.35                                                      Cl.sub.2 N.sub.3 O.sub.2                                                      requires C, 65.11; H, 6.83; N,                                                8.14%. .sup.1 H-NMR(CDCl.sub.3)                                               : δ = 1.5-1.75 (m,3H),                                                  1.95-2.3(m,8H), 2.35-2.5                                                      (m,4H), 2.6-2.7(m,2H), 2.8-2.9                                                (m,1H), 3.2-3.35(m,3H), - #                                                   3.45-3.5 (m,1H),                                                              3.65-3.7(m,4H), 4.3 (d,1H),                                                   4.8(d,1H), 6.8-6.85 (m,1H),                                                   7.0-7.3(m,6H) ppm.                 79                                                                               2 #STR267##                                                                             5 #STR268##                                                                           7 #STR269##   -- 515 (m).sup.+                                                                      Found: C, 64.74; H, 6.78; N,                                                  8.32. C.sub.28 H.sub.35                                                       Cl.sub.2 N.sub.3 O.sub.2                                                      requires C, 65.11; H, 6.83; N,                                                8.14%. .sup.1 H-NMR(CDCl.sub.3)                                               : δ = 1.45-1.6 (m,1H),                                                  1.6-1.8(m,2H), 1.95-2.1                                                       (m,4H), 2.1-2.5(m,8H), 2.6-2.7                                                (m,2H), 2.8-2.9(m,1H), - #                                                    3.1-3.2 (m,1H),                                                               3.25-3.35(m,2H), 3.5-3.55                                                     (m,1H), 3.7-3.75(m,4H), 4.35                                                  (d,1H), 5.0(d,1H), 6.75-6.8                                                   (m,1H), 7.0-7.05(m,1H),                                                       7.15-7.3 (m,5H) ppm.               80.sup.1                                                                         3 #STR270##                                                                             5 #STR271##                                                                           7 #STR272##   -- 545 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3):                                                     δ = 1.2-1.45 (m,2H),                                                    1.6-1.9(m,6H), 1.95-2.35                                                      (m,13H), 2.7-2.8(m,2H),                                                       2.85-3.0 (m,1H),                                                              3.15-3.25(m,1H), 3.3-3.45                                                     (m,4H), 3.5-3.6(d,1H),                                                        3.65-3.7 (m,4H),                                                              7.05-7.1(d,1H), 7.3-7.35                                                      (s,1H), 7.4-7.45(d,1H) ppm.        81.sup.1                                                                         4 #STR273##                                                                             6 #STR274##                                                                           7 #STR275##   -- 474 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3):                                                     δ = 0.95-1.1 (m,2H),                                                    1.15-1.3(m,4H), 1.5-1.85                                                      (m,10H), 1.95-2.4(m,6H),                                                      2.7-2.8 (m,2H),                                                               2.9-2.95(m,1H), 3.05-3.15                                                     (m,1H), 3.3-3.7(m,10H),                                                       7.15-7.35 (m,4H) ppm.              82.sup.2,3                                                                       4 #STR276##                                                                             6 #STR277##                                                                           8 #STR278##   -- 502.8 (m + 1).sup.+                                                                Found: C, 64.27; H, 8.59; N,                                                  7.78. C.sub.29 H.sub.44                                                       ClN.sub.3 O.sub.2.0.6 CH.sub.2                                                Cl.sub.2 requires: C, 64.27;                                                  H, 8.25; N, 7.60%. .sup.1                                                     H-NMR(CDCl.sub.3): δ =                                                  0.9-1.1 (m,2H), 1.1-1.3(m,2H),                                                1.5-2.2 (m,19H),                                                              2.3-2.6(m,3H), 2.6-2.8  -                                                     #(m,2H), 2.8-2.85(m,1H),                                                      3.0-3.1 (m,1H),                                                               3.15-3.3(m,1H), 3.3-3.6                                                       (m,9H), 7.1-7.2(m,2H), 7.2-7.4                                                (m,2H) ppm.                        83.sup.2,3                                                                       4 #STR279##                                                                             6 #STR280##                                                                           9 #STR281##   -- 488.9 (m + 1).sup.+                                                                .sup.1 H-NMR(CDCl.sub.3):                                                     δ = 0.9-1.05 (m,2H),                                                    1.1-1.3(m,4H), 1.5-2.2                                                        (m,20H), 2.3-2.4(m,1H),                                                       2.45-2.6 (m,2H),                                                              2.6-2.8(m,2H), 2.8-2.9 (m,1H),                                                2.0-3.1(m,1H), 3.3-3.6 (m,4H),                                                3.6-3.8(m,1H), 7.15 (d,2H),                                                   7.3(d,2H) ppm.                     84.sup.2,4                                                                       4 #STR282##                                                                             5 #STR283##                                                                           9 #STR284##   -- 522 (m + 1).sup.+                                                                  Found: C, 61.71; H, 8.00; N,                                                  7.63. C.sub.28 H.sub.41                                                       Cl.sub.2 N.sub.3 O.sub.2.0.31                                                 CH.sub.2 Cl.sub.2 requires: C,                                                61.93; H, 7.64; N, 7.65%.                                                     .sup.1 H-NMR(CDCl.sub.3):                                                     δ = 0.9-1.1 (m,2H),                                                     1.1-1.5(m,4H), 1.5-2.3                                                        (m,19H), 2.35-2.45(m,1H), -                                                   #2.5-2.6 (m,2H),                                                              2.65-2.75(m,2H), 2.8-2.9                                                      (m,1H), 3.1-3.3(m,1H), 3.3-3.4                                                (m,4H), 3.5-3.6(m,1H),                                                        3.65-3.75 (m,1H), 7.05(d,1H),                                                 7.2-7.25 (m,1H), 7.3(d,1H)                                                    ppm.                               85.sup.2,4                                                                       4 #STR285##                                                                             5 #STR286##                                                                           8 #STR287##   -- 536 (m).sup.+                                                                      Found: C, 64.06; H, 7.81; N,                                                  7.58. C.sub.29 H.sub.43                                                       N.sub.3 Cl.sub.2 O.sub.2.0.125                                                CH.sub.2 Cl.sub.2 requires; C,                                                63.93; H, 7.97; N, 7.68%.                                                     .sup.1 H-NMR(CDCl.sub.3):                                                     δ = 0.9-1.1 (m,2H),                                                     1.1-1.3(m,3H), 1.5-2.2                                                        (m,19H), 2.3-2.6(m,3H), - #                                                   2.6-2.75 (m,2H),                                                              2.8-2.9(m,1H), 3.1-3.25                                                       (m,2H), 3.25-3.45(m,7H),                                                      3.5-3.6 (m,1H), 7.05(d,1H),                                                   7.2-7.3 (m,1H), 7.35-7.4(m,1H)                                                ppm.                               86.sup.2,4                                                                       4 #STR288##                                                                             5 #STR289##                                                                           0 #STR290##   -- 550 (m).sup.+                                                                      Found: C, 64.21; H, 8.03; N,                                                  7.37. C.sub.30 H.sub.45                                                       N.sub.3 Cl.sub.2 O.sub.2.0.125                                                CH.sub.2 Cl.sub.2 requires: C,                                                64.47; H, 8.03; N, 7.49%.                                                     .sup.1 H-NMR(CDCl.sub.3):                                                     0.9-1.1(m,2H), 1.1-1.35(m,6H),                                                1.5-2.2(m,19H), 2.3-2.5(m,1H),                                                2.5-2.6(m,2H), 2.6-                                                           2.75(m,2H), -                                                                 # 2.8-2.95(m,1H), 3.1-                                                        3.2(m,1H), 3.2-3.6(m,8H), 7.05                                                (d,1H), 7.2-7.25(m,1H),                                                       7.4(d,1H) ppm.                     87.sup.2,4                                                                       4 #STR291##                                                                             5 #STR292##                                                                           1 #STR293##   -- 565 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3):                                                     δ = 0.9-1.1 (m,4H),                                                     1.1-1.25(m,3H), 1.5-                                                          2.2(m,23H), 2.3-2.5(m,1H),                                                    2.5- 2.6(m,2H), 2.6-2.8(m,2H),                                                2.8- 2.95(m,1H),                                                              3.1-3.2(m,1H), 3.25-                                                          3.5(m,6H), 3.5-3.6(m,1H), 7.05                                                (d,1H), 7.3-7.35(m,1H), - #                                                   7.4-7.45 (m,1H) ppm.               88.sup.4,5                                                                       4 #STR294##                                                                             5 #STR295##                                                                           2 #STR296##   -- 578 (m).sup.+                                                                      .sup.1 H-NMR(CDCl.sub.3):                                                     δ = 0.9-1.0 (m,1H),                                                     1.15(s,9H), 1.4-1.8 (m,17H),                                                  1.8-2.2(m,6H), 2.3-2.45                                                       (m,1H), 2.5-2.6(m,2H),                                                        2.65-2.8 (m,2H),                                                              2.8-3.0(m,1H), 3.2-3.4 (m,1H),                                                3.3-3.45(m,5H), 3.5-                                                          3.6(m,1H), 7.05(d,1H),                                                        7.3-7.35  - #(m,1H),                                                          7.4-7.45(m,1H) ppm.                89.sup.2,3                                                                       4 #STR297##                                                                             6 #STR298##                                                                           3 #STR299##   -- 551 (m).sup.+                                                                      .sup.1 H-NMR(CDCl.sub.3):                                                     δ = 0.9-1.0 (m,4H),                                                     1.1-1.3(m,5H), 1.5-1.9 (m,7H),                                                1.9-2.25(m,5H), 2.3-2.4                                                       (m,4H), 2.75(s,3H), 2.95-3.1                                                  (m,2H), 3.1-3.3(m,4H), 3.3-3.6                                                (m,5H), 7.15(d,2H), 7.35(d,2H)                                                ppm.                               90.sup.2,4                                                                       4 #STR300##                                                                             5 #STR301##                                                                           4 #STR302##   -- 586 (m + 1).sup.+                                                                  Found: C, 56.54; H, 7.42; N,                                                  8.78. C.sub.28 H.sub.42                                                       N.sub.4 O.sub.3 SCl.sub.2.0.188                                                CH.sub.2 Cl.sub.2 requires:                                                  C, 56.28; H, 7.10; N, 9.31%.                                                  .sup.1 H-NMR(CDCl.sub.3):                                                     δ = 0.9-1.1 (m,2H),                                                     1.1-1.35(m,3H), 1.5-1.9                                                       (m,8H), 1.9-2.3(m,5H), - #                                                    2.3-2.5 (m,5H), 2.7-2.8(m,5H),                                                2.9-3.05 (m,1H),                                                              3.1-3.3(m,5H), 3.3-3.5 (m,4H),                                                3.5-3.6(m,1H), 7.05 (d,1H),                                                   7.3-7.35(m,1H), 7.4(d,1H)                                                     ppm.                               91.sup.2,4                                                                       4 #STR303##                                                                             5 #STR304##                                                                           5 #STR305##   -- 611 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3):                                                     δ = 0.9-1.05 (m,2H),                                                    1.1-1.25(m,3H), 1.5-1.85                                                      (m,8H), 1.95-2.45(m,10H),                                                     2.65- 2.75(m,2H),                                                             1.85-1.95(m,1H), 3.1-                                                         3.2(m,1H), 3.3-3.4(m,5H),                                                     3.5-3.55 (m,2H),                                                              3.6-3.85(m,2H), 7.05-7.1                                                      (m,1H), 7.3-7.4(m,7H) ppm.         92.sup.2,4                                                                       4 #STR306##                                                                             5 #STR307##                                                                           6 #STR308##   -- 586 (m + 1).sup.+                                                                  Found: C, 51.52; H, 6.60; N,                                                  11.09. C.sub.27 H.sub.41                                                      Cl.sub.2 N.sub.5 O.sub.3                                                      S.0.63 CH.sub.2 Cl.sub.2                                                      requires: C, 51.86; H, 6.70;                                                  N, 10.95%. .sup.1 H-NMR(CDCl.su                                               b.3): δ = 0.95-1.05                                                     (m,2H), 1.1-1.3(m,3H),                                                        1.55-1.85 (m,8H),                                                             1.95-2.25(m,5H), - # 2.35-                                                    2.45(m,5H), 2.7-2.75(m,2H),                                                   2.9- 2.95(m,1H),                                                              3.1-3.25(m,5H), 3.3-                                                          3.4(m,4H), 3.5-3.55(m,1H),                                                    4.35 (br.s,2H),                                                               7.05-7.10(m,1H), 7.25-                                                        7.45(m,2H) ppm.                    93.sup.2,4                                                                       4 #STR309##                                                                             5 #STR310##                                                                           7 #STR311##   -- 564 (m + 1).sup.+                                                                  Found: C, 58.33; H, 7.37; N,                                                  11.67. C.sub.29 H.sub.43                                                      Cl.sub.2 N.sub.5 O.sub.2.0.5                                                  CH.sub.2 Cl.sub.2 requires: C,                                                58.30; H, 7.31; N, 11.54%.                                                    .sup.1 H-NMR(CDCl.sub.3):                                                     δ = 0.95-1.05 (m,2H),                                                   1.15-1.30(m,3H), 1.5-                                                         1.8(m,8H), 1.95-2.30(m,9H), -                                                 # 2.3- 2.4(m,1H),                                                             2.65-2.75(m,2H), 2.8-                                                         2.85(m,3H), 2.9-2.95(m,1H),                                                   3.1- 3.2(m,1H), 3.3-3.4(m,8H),                                                3.5- 3.55(m,1H),                                                              4.35-4.4(m,1H), 7.05-                                                         7.1(m,1H), 7.25-7.4(m,2H)                                                     ppm.                               94.sup.2,4                                                                       4 #STR312##                                                                             5 #STR313##                                                                           8 #STR314##   -- 624 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3):                                                     δ = 0.95-1.1 (m,2H),                                                    1.15-1.3(m,3H), 1.5-1.8                                                       (m,10H), 1.95-2.25(m,11H),                                                    2.35- 2.45(m,1H),                                                             2.7-2.8(m,3H), 2.9- 3.0(m,1H),                                                3.1-3.2(m,1H), 3.3-                                                           3.55(m,5H), 7.1-7.7(m,7H)                                                     ppm.                               95.sup.4,5                                                                       4 #STR315##                                                                             5 #STR316##                                                                           9 #STR317##   -- --   .sup.1 H-NMR(CDCl.sub.3):                                                     δ = 0.95-1.1 (m,2H),                                                    1.15-1.3(m,6H), 1.55-                                                         2.3(m,20H), 2.35-2.45(m,1H),                                                  2.6- 2.75(m,4H),                                                              2.8-2.9(m,1H), 3.1- 3.2(m,1H),                                                3.3-3.5(m,4H), 3.55-                                                          3.6(m,1H), 4.05-4.15(m,2H),                                                   7.05- 7.1(m,1H),                                                              7.25-7.45(m,2H) ppm.               96.sup.2,4                                                                       4 #STR318##                                                                             5 #STR319##                                                                           0 #STR320##   -- 621 (m + 1).sup.+                                                                  Found: C, 61.30; H, 7.91; N,                                                  8.44. C.sub.33 H.sub.50                                                       Cl.sub.2 N.sub.4 O.sub.3.0.38                                                 CH.sub.2 Cl.sub.2 requires: C,                                                61.33; H, 7.83; N, 8.57%.                                                     .sup.1 H-NMR(CDCl.sub.3):                                                     δ = 0.9-2.2 (m,35H),                                                    2.3-2.45(m,1H), 2.55-                                                         2.7(m,2H), 2.8-2.9(m,1H), - #                                                 3.1- 3.15(m,1H),                                                              3.3-3.55(m,6H),  4.35(br. s,                                                  1H), 7.05-7.1(m,1H),                                                          7.25-7.4(m,2H)                     __________________________________________________________________________                                               ppm.                                Footnotes                                                                     .sup.1 3 mol. equiv. of the azetidine derivative starting material and 3      mol. equiv. of triethylamine were used in the reaction.                       .sup.2 The ditrifluoroacetate salt of the azetidine starting material was     used.                                                                         .sup.3 10 mole equivalents of potassium carbonate were used instead of        triethylamine as the acid acceptor.                                           .sup.4 About 2.5 mole equivalents of potassium carbonate were used instea     of triethylamine as the acid acceptor.                                        .sup.5 The dihydrochloride salt of the azetidine starting material was        used.                                                                    

EXAMPLE 971-Benzyl-5-(2-[3-morpholinoazetidin-1-yl]ethyl)-5-phenyl-2-piperidone##STR321##

The piperidone (see Example 18) (95 mg, 0.2 mmol) was dissolved inethanol which had been saturated with ammonia (20 ml) and Raney nickel(10 mg) was added. The mixture was then stirred at 50° C. under anatmosphere of hydrogen at 345 kPa (50 psi) for 10 hours. The catalystwas then removed by filtration and 5% palladium on carbon (10 mg) added.The mixture was then stirred for a further sixteen hours at 50° C. and345 kPa under an atmosphere of hydrogen. The catalyst was then removedby filtration, the filtrate concentrated under reduced pressure and theresidue chromatographed using silica gel eluting with a solvent gradientof methanol:dichloromethane (0:100 to 9:91, by volume) to give the titlecompound (19 mg). TLC R_(f) =0.3 (silica, methanol:dichloromethane, 1:9by volume). LRMS m/z=434(m)⁺. Found: C, 66.22; H, 8.26; N, 8.60. C₂₇ H₃₅N₃ O₂.3H₂ O requires C, 66.50; H, 8.47; N, 8.62%.

¹ H-NMR (CDCl₃):δ=0.8-1.0 (d,2H), 1.1-1.4 (m,1H), 1.9-2.6 (m,12H),2.6-2.8 (m,1H), 3.2-3.4 (m,2H), 3.5-3.8 (m,5H), 4.5 (d,1H), 4.8 (d,1H),6.95-7.1 (m,2H), 7.2-7.4 (m,8H) ppm.

EXAMPLE 981-Benzyl-5-(3,4-dichlorophenyl)-5-(2-[3-piperazinoazetidin-1-yl]ethyl)-2piperidone ##STR322##

To a solution of the piperazine (see Example 7) (101 mg, 0.16 mmol) indry dichloromethane (3.5 ml) under an atmosphere of nitrogen at roomtemperature was rapidly added trifluoroacetic acid (3.5 ml, 45 mmol).The reaction mixture was stirred for a further twenty minutes and thenthe solvent evaporated under reduced pressure. The reaction wasazeotroped twice using dichloromethane (50 ml) to remove the excesstrifluoroacetic acid. The reaction mixture was basified (pH 9) usingsaturated aqueous sodium carbonate solution (30 ml) and the aqueousphase extracted with ethyl acetate (4×50 ml). The organic extracts werecombined, dried over anhydrous magnesium sulphate and evaporated todryness under reduced pressure. The resulting foam was dissolved indichloromethane (0.25 ml), filtered and the solvent removed from thefiltrate under reduced pressure to give the title compound (88 mg). TLCR_(f) =0.16 (silica, methanol:dichloromethane:conc. aqueous ammoniasolution, 9:90:1, by volume). LRMS m/z=467(m)⁺. Found: C, 55.15; H,5.74; N, 6.84. C₂₇ H₃₄ N₄ Cl₂ O.0.125 CH₂ Cl₂ requires C, 54.42; H,5.93; N, 8.90%.

¹ H-NMR (CDCl₃):δ=1.2-1.3 (m,1H), 1.4-1.6 (m,2H), 1.9-2.3 (m,6H),2.3-2.5 30 (m,4H), 2.7-2.8 (m,2H), 2.9-3.25 (m,5H), 3.25 (d,1H), 3.3-3.5(m,2H), 3.55 (d,1H), 4.4 (d,1H), 4.8 (d,1H), 6.8 (d,1H), 7.05 (s,1H),7.2-7.4 (m,6H) ppm.

EXAMPLE 991-(2,4-Dichlorobenzyl)-5-(3,4-dichlorophenyl)-5-(2-[3-morpholinoazetidin-1-yl]ethyl)-2-piperidone##STR323##

To a stirred solution of powdered potassium hydroxide (110 mg, 4 mol.equiv.) in dry dimethylsulphoxide (4 ml) was added a solution of thepiperidone (see Example 1) (200 mg, 0.49 mmol) in dry dimethylsulphoxide(4 ml) followed by 2,4-dichlorobenzyl chloride (0.068 ml, 1 mol. equiv.)and potassium iodide (8 mg, 0.1 mol. equiv.). The mixture was thenallowed to stir at room temperature for sixteen hours. Ethyl acetate (50ml) was then added, the mixture washed with water (3×50 ml) and theorganic phase dried over anhydrous magnesium sulphate. The solution wasthen filtered, the solvent removed from the filtrate under reducedpressure and the residue chromatographed using silica gel eluting with asolvent gradient of ethyl acetate:methanol:diethylamine (100:0:0 to100:5:1, by volume) to give the title compound (49 mg). LRMSm/z=572(m+1)⁺.

¹ H-NMR (CDC₃):δ=1.55-1.8 (m,2H), 1.95-2.3 (m,10H), 2.4-2.5 (m,1H),2.65-2.7 (m,1H), 2.85-2.9 (m,1H), 3.3-3.4 (m,3H), 3.6-3.7 (m,5H), 4.6(d,1H), 4.85 (d,1H), 6.9-6.95 (m,1H), 7.05 (m,1H), 7.2-7.4 (m,4H) ppm.

EXAMPLE 1005-(3,4-Dichlorophenyl)-1-(4-fluorobenzyl)-5-(2-[3-morpholinoazetidin-1yl]ethyl)-2-piperidone ##STR324##

To dry dimethylsulphoxide (3 ml) at room temperature was added powderedpotassium hydroxide (104 mg, 4 mol. equiv.) and the mixture was allowedto stir at room temperature for five minutes. A solution of thepiperidone (see Example 1) (240 mg, 0.46 mmol) in dimethylsulphoxide (5ml) was then added followed by 4-fluorobenzyl bromide (0.058 ml, 1 mol.equiv.) and the mixture allowed to stir at room temperature for fiftyminutes. The reaction was poured into ethyl acetate (40 ml), washed withwater (3×40 ml) and the organic phase dried over anhydrous magnesiumsulphate. The solution was then filtered, the solvent removed from thefiltrate under reduced pressure and the residue chromatographed onsilica gel eluting with a solvent gradient of ethylacetate:methanol:diethylamine (100:0:0 to 10:1:2 to 20:3:1, by volume)to give the title compound (lOOmg). LRMS m/z=521(m+1)⁺. TLC Rf=0.4(silica, ethyl acetate:methanol:diethylamine, 20:3:1, by volume). Found:C, 61.46; H, 6.27; N, 7.55. C₂₇ H₃₂ Cl₂ N₃ O₂ F requires C, 62.31; H,6.20; N, 8.07%.

¹ H-NMR (CDCl₃):δ=1.5-1.85 (m,4H), 1.95-2.2 (m,8H), 2.6-2.75 (m,2H),2.8-2.9 (m,1H), 3.15-3.35 (m,4H), 3.65-3.75 (m,4H), 4.3 (d,1H), 4.8(d,1H), 6.8-7.3 (m,7H) ppm.

EXAMPLES 101 and 102

The compounds of the following tabulated Examples of the generalformula: ##STR325## were prepared by a similar method to that of Example100 using the same piperidone starting material and3,5-di(trifluoromethyl)benzyl bromide or2-methanesulphonyloxyethylcyclopropane (see Preparation 157), asappropriate.

    __________________________________________________________________________    Ex.                LRMS                                                       No.                                                                              R               m/z  Analysis/.sup.1 H-NMR                                 __________________________________________________________________________    101                                                                              8 #STR326##     638 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 1.5-1.8(m,                                5H), 2.0-2.15(m, 3H), 2.15- 2.3(m, 5H),                                       2.65-2.75(m, 2H), 2.85-2.9(m, 1H), 3.3-3.35 (m,                               3H), 3.6-3.7(m, 4H), 4.6-4.8(m, 2H), 6.85-6.9(m,                              1H), 7.1- 7.15(m, 1H), 7.3-7.35(m, 1H), 7.75(s,                               2H), 7.85(s, 1H) ppm.                                 102                                                                              9 #STR327##     480 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 0.1-0.15(m,                               2H), 0.45-0.5(m, 2H), 0.6- 0.7(m, 1H),                                        0.85-0.95(m, 1H), 1.45-1.55(m, 2H), 1.6-1.7 (m,                               2H), 1.85-1.9(m, 1H), 1.95-2.4(m, 10H),                                       2.75-2.8(m, 2H), 2.9-2.95(m, 1H), 3.3-3.4(m, 3H),                             3.55-3.7(m, 5H), 7.1-7.15 (m, 1H), 7.3-7.4(m, 2H)                             ppm.                                                  __________________________________________________________________________

EXAMPLE 1031-Benzyl-5-(3,4-dichlorophenyl)-5-(2-[3-(1-oxothiomorpholino)azetidin-1-yl]ethyl)-2-piperidone##STR328##

To an ice cooled solution of methanol (7 ml), the thiomorpholine (seeExample 2) (0.76 ml, 1.0 mol. equiv.), acetonitrile (0.09 g, 1.5 mol.equiv.) and potassium carbonate (0.147 g, 0.72 mol. equiv.) was added,over thirty minutes, a solution of 30% w/v hydrogen peroxide in water(0.175 g, 1.05 mol. equiv.) in methanol (5 ml). The reaction was stirredat 0° C. for two hours and then allowed to warm to room temperature andstirred for a further sixteen hours. The majority of the solvent wasthen removed under reduced pressure at room temperature. Saturatedaqueous sodium bicarbonate solution (20 ml) was added and the mixtureextracted with ethyl acetate (3×50 ml). The combined organic layers weredried over magnesium sulphate and evaporated under reduced pressure. Theoil obtained was purified by flash column chromatography on silica geleluting with methanol:dichloromethane (1:9, by volume) to give the titlecompound (121 mg). TLC R_(f) 0.10 (silica, methanol:dichloromethane,1:9, by volume). LRMS m/z=534(m+1)⁺. Found: C, 57.91; H, 5.77; N, 7.58.C₂₇ H₃₃ N₃ C₁₂₀₂ S. 0.37 CH₂ Cl₂ requires C, 58.05; H, 6.01, N, 7.42%.

¹ H-NMR (CDCl₃):δ=1.1-1.3 (m,1H), 1.4-1.8 (m,1H), 1.9-2.3 (m,5H),2.4-2.6 (m,5H), 2.6-2.7 (m,6H), 2.7-2.9 (m,1H), 2.9-3.1 (m,1H), 3.2-3.4(m,2H), 3.4-3.6 (m,1H), 4.4 (d,1H), 4.8 (d,1H), 6.8 (d,1H), 7.1 (s,1H),7.3-7.4 (m,6H) ppm.

EXAMPLE 1041-Benzyl-5-(3,4-dichlorophenyl)-5-(2-[3-(endo-3-hydroxy-8-azabicyolo[3,2,1]oct-8-yl)azetidin-1-yl]ethyl)-2-piperidone##STR329##

A mixture of the piperidone (see Example 24) (78 mg), 6N aqueous sodiumhydroxide solution (0.5 ml) and methanol (1.5 ml) was stirred at roomtemperature for sixteen hours. The solution was concentrated underreduced pressure and water (5 ml) and dichloromethane (10 ml) were thenadded. The layers were separated and the aqueous phase was furtherextracted with dichloromethane (2×10 ml). The combined organic layerswere dried over anhydrous sodium sulphate and then filtered. The solventwas removed from the filtrate under reduced pressure to give the titlecompound as a white foam (67 mg). LRMS m/z=543(m+1)⁺. Found: C, 62.15;H, 6.11; N, 7.43. C₃₀ H₃₉ Cl₂ N₃ O. 0.56 CH₂ Cl₂ requires C, 62.40; H,6.87; N, 7.16%.

¹ H-NMR (CDCl₃):δ=1.5-2.2 (m,18H), 2.4-2.5 (m,1H), 2.6-2.7 (m,2H), 2.95(br.s,2H), 3.1-3.2 (m,1H), 3.25-3.35 (m,3H), 3.5-3.6 (m,1H), 3.95-4.05(m,1H), 4.2(d,1H), 4.8 (d,1H), 6.75-6.8 (m,1H), 7.1 (d,1H), 7.2-7.4(m,6H) ppm.

EXAMPLE 1055(S)-1-Cyclopropylmethyl-5-(3,4-dichlorophenyl)-5-(2-[3-(piperazin-1-yl)azetidin-1-yl]ethyl)-2-piperidone##STR330##

To a solution of the compound of Example 32 (1.36 g, 2.5 mmol) inmethanol (15 ml) was added 10% w/w aqueous sodium hydroxide solution(5.44 ml). The mixture was heated under reflux for 48 hours. Themethanol was then removed by evaporation under reduced pressure and theresidue acidified to pH7 using 2N aqueous hydrochloric acid solution.The mixture was extracted with dichloromethane (2×40 ml). The combinedorganic extracts were evaporated to dryness under reduced pressure togive the title compound as a white foam (0.5 g).

TLC Rf=0.1 (silica, concentrated aqueous ammonia:methanol:dichloromethane, 20:80:320, by volume). LRMS m/z=465 (m)⁺.

¹ H-NMR (CDCl₃):δ=0.2-0.4 (m,2H), 0.5-0.7 (m,2H), 1.0-1.1 (m,1H),1.6-2.6 (m,17H), 2.7-2.8 (m,2H), 2.9-3.05 (m,2H), 3.1-3.2 (m,1H),3.4-3.6 (m,3H), 3.7-3.85 (m,1H), 7.1-7.2 (m,1H), 7.3-7.5 (m,2H) ppm.

EXAMPLE 1065(S)-1-(2-Cyclopropylethyl)-5-(2-[3-(4-cyclopropylmethylaminopiperidin-1-yl)azetidin-1-yl]ethyl)-5-(3,4-dichlorophenyl)-2-piperidone##STR331##

To a solution of the compound of Example 115 (0.1 g, 0.11 mmol) intetrahydrofuran (3 ml) under nitrogen were addedcyclopropylcarboxaldehyde (8 mg) and triethylamine (0.017 ml). Afterstirring for five minutes, sodium triacetoxyborohydride (32 mg) andglacial acetic acid (0.007 ml) were added and the reaction stirred atroom temperature for sixteen hours. The reaction mixture wasconcentrated under reduced pressure and the residue partitioned betweendichloromethane (12 ml) and 10% w/w aqueous sodium carbonate solution (4ml). The layers were separated and the aqueous phase was extracted withdichloromethane (2×10 ml). The combined organic extracts were dried overanhydrous magnesium sulphate, filtered and the solvent removed from thefiltrate by evaporation under reduced pressure. The residue waschromatographed on silica gel eluting with dichloromethane:methanol:concentrated ammonia solution, 89:10:1, by volume) to give the titlecompound (37 mg). TLC Rf=0.18 (silica,dichloromethane:methanol:concentrated ammonia solution, 89:10:1, byvolume). LRMS m/z=547 (m+1)⁺.

¹ H-NMR (CDCl₃):δ=0.1-0.15(m,4H), 0.4-0.5(m,4H), 0.6-0.7(m,1H), 0.9-1.0(m, 1H), 1.25-1.4(m,2H), 1.45-1.7(m,4H), 1.75-1.9(m,5H), 1.95-2.2(m,5H),2.3-2.45(m,4H), 2.6-2.7(m,4H), 2.8-2.9(m,1H), 3.3-3.4(m,4H),3.5-3.7(m,2H), 7.0-7.4(m,3H) ppm.

EXAMPLES 107 and 108

The compounds of the following tabulated Examples of the generalformula: ##STR332## were prepared by a similar method to that of Example106 using the appropriate amine starting materials (see Examples 105 and113) and cyclopropylcarboxaldehyde.

    __________________________________________________________________________    Ex.                          LRMS                                             No.                                                                              R      --X.sup.1 --R.sup.2                                                                           m.p.                                                                             m/z  Analysis/.sup.1 H-NMR                       __________________________________________________________________________    107                                                                              1 #STR333##                                                                          3 #STR334##     -- 611 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ =                                           0.1-0.15(m,2H), 0.45- 0.5(m,2H),                                              0.85-1.0(m,1H), 1.25-2.55 (m,27H),                                            2.6-2.7(m,4H), 2.8-2.9(m,1H), 3.2-                                            3.25(m,1H), 3.3-3.35(m,4H), 3.55-3.6                                          (m,1H), 7.1-7.4(m,3H) ppm.                  108                                                                              2 #STR335##                                                                          4 #STR336##     -- 519 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ =                                           0.15-0.4(m,3H), 0.55- 0.7(m,3H),                                              0.85-1.1(m,2H), 1.6-1.9(m,2H),                                                2.0-2.2(m,4H), 2.5-2.6(m,10H), 2.7-3.0                                        (m,6H), 3.05-3.2(m,2H), 3.4-3.5(m,4H),                                        3.7- 3.8(m,1H), 7.15-7.4(m,3H)              __________________________________________________________________________                                      ppm.                                    

EXAMPLE 1095(S)-5-(2-[3-(4-Aminosulphonylpiperazin-1-yl)azetidin-1-yl]ethyl)-1-(5-carboxypentyl)-5-(3,4-dichlorophenyl)-2-piperidoneditrifluoroacetate ##STR337##

To a solution of the compound of Example 57 (30 mg, 0.045 mmol) indichloromethane (1 ml) at 0° C. under nitrogen was added trifluoroaceticacid (0.05 ml). The mixture was stirred for 2 hours at room temperature.The dichloromethane solvent was removed under reduced pressure to give agum which crystallised following trituration with diethyl ether toprovide the title compound as a white solid (20 mg). TLC Rf=0.48(silica, methanol: dichloromethane, 1:9, by volume). LRMS m/z=604(m+1)⁺. Found: C,42.47; H,4.73; N,7.90. C₂₆ H₃₉ Cl₂ N₅ O₅ S. 2 CF₃ CO₂H.H₂ O requires: C,42.46; H,4.88; N,8.25%.

EXAMPLE 1105-(2-[3-(4-Carboxypiperidin-1-yl)azetidin-1-yl]ethyl)-1-cyclohexylmethyl-5-(3,4-dichlorophenyl)-2-piperidone##STR338##

To a solution of the compound of Example 95 in ethanol (1 ml) was added1 N aqueous sodium hydroxide solution (0.24 ml) and the mixture stirredat room temperature for sixteen hours. The ethanol was removed underreduced pressure and water (1 ml) was added to the residue. The solutionwas adjusted to pH5 using 2N aqueous hydrochloric acid solution to givean oil which crystallised when scratched. The resulting solid wasfiltered off, triturated with water (2×3 ml) followed by diethyl ether(3×3 ml), then dried under reduced pressure at 70° C. to give the titlecompound (40 mg). LRMS m/z=550 (m+1)⁺. Found: C,55.80; H,7.14; N,6.44.C₂₉ H₄₁ N₃ Cl₂ O₃.0.75 H₂ O. NaCl requires: C,55.95; H,6.88; N,6.75%.

EXAMPLE 1115(S)-(2-[3-(4-Carboxypiperidin-1-yl)azetidin-1-yl]ethyl)-1-cyclopropylmethyl-5-(3,4-dichlorophenyl)-2-piperidone

This compound was prepared by a similar method to that of Example 110using the appropriate methyl ester starting material (see Example 59)and 3.8 mole equivalents of the aqueous sodium hydroxide solution. LRMSm/z=508(m)⁺.

EXAMPLE 112(S)-5-(2-[3-(4-Aminopiperidin-1-yl)azetidin-1-yl]ethyl)-1-cyclopropylmethyl-5-(3,4-dichlorophenyl)-2-piperidonetristrifluoroacetate ##STR339##

To a solution of the compound of Example 48 (1.4 g, 24.1 mmol) indichloromethane (20 ml) at +40° C. under nitrogen was addedtrifluoroacetic acid (6.6 ml) and the reaction stirred at roomtemperature for one hour. The solvent and excess trifluoroacetic acidwere removed under reduced pressure to give the title compound (907 mg).LRMS m/z=479 (m+1)⁺.

EXAMPLES 113 to 115

The compounds of the following tabulated examples of the generalformula: ##STR340## were prepared by a similar method to that of Example112 using the appropriate t-butoxycarbonyl-protected amine (see Examples46, 51 and 54) and trifluoroacetic acid.

    __________________________________________________________________________    Ex.             LRMS                                                          No.                                                                              R         m.p.                                                                             m/z  Analysis/.sup.1 H-NMR                                    __________________________________________________________________________    113                                                                              5 #STR341##                                                                             -- 557 (m + 1).sup.+                                                                  Found: C, 44.81; H, 4.77; N, 6.11. C.sub.28 H.sub.40                          Cl.sub.2 F.sub.2 N.sub.4 O. 3CF.sub.3 CO.sub.2 H.                             0.25CH.sub.2 Cl.sub.2 requires: C, 45.39; H, 4.82;                            N, 6.23%.                                                114                                                                              6 #STR342##                                                                             -- 535 (m + 1).sup.+                                                                  Found: C, 46.11; H, 5.27; N, 6.01. C.sub.29 H.sub.42                          Cl.sub.2 N.sub.4 O. 3CF.sub.3 CO.sub.2 H. 2H.sub.2 O                          requires: C, 46.11; H, 5.42; N, 6.15%.                   115                                                                              7 #STR343##                                                                             -- 493 (m + 1).sup.+                                                                  --                                                       __________________________________________________________________________

EXAMPLE 1165-(2-[3-(4-Aminopiperidin-1-yl)azetidin-1-yl]ethyl)-1-cyclohexylmethyl-5-(3,4-dichlorophenyl)-2-piperidonetristrifluoroacetate ##STR344##

To a solution of the compound of Example 96 (0.53 g, 0.85 mmol) indichloromethane (5 ml) at 0° C. under nitrogen was slowly addedtrifluoroacetic acid and the solution allowed to stir at roomtemperature for 1 hour. The excess trifluoroacetic acid anddichloromethane were removed under reduced pressure, the residue treatedwith dichloromethane (5 ml) and the solvent removed under reducedpressure. The residue was triturated with diethyl ether, filtered andthe solid obtained rapidly washed with diethyl ether, then dried underreduced pressure at 70° C. to give the title compound (580 mg). LRMSm/z=522 (m+1 )⁺.

¹ H-NMR (CDCl₃)/d₆ -DMSO):δ=0.75-0.9(m,2H), 0.95-1.1(m,3H), 1.35-4.0(m,32H), 6.95-7.0(m, 1H), 7.15-7.20(m, 1H), 7.30-7.35(m,1H),8.35(br.s,2H) ppm.

EXAMPLE 1171-Cyclohexylmethyl-5-(3,4-dichlorophenyl)-5-(2-[3-(4-methanesulphonamidopiperidin-1-yl)azetidin-1-yl]ethyl)-2-piperidone##STR345##

To a solution of the compound of Example 116 (0.29 g, 0.34 mmol) andtriethylamine (0.23 ml) in dichloromethane (6 ml) at 0° C. undernitrogen was added methanesulphonyl chloride (0.035 ml). The mixture wasallowed to stir at room temperature for sixteen hours. Thedichloromethane was removed under reduced pressure, the residue taken upin ethyl acetate (30 ml) and washed with 1% w/w aqueous sodiumbicarbonate solution (5 ml). The organic phase was dried using anhydrousmagnesium sulphate, filtered and the solvent removed from the filtrateunder reduced pressure to give an oil. This oil was chromatographed onsilica gel eluting with methanol:dichloromethane (1:9, by volume) togive the title compound (85 mg). TLC Rf 0.25 (silica, methanol:dichloromethane, 1:9, by volume).

¹ H-NMR (CDCl₃):δ=0.9-1.1 (m,2H), 1.15-1.30(m,3H), 1.45-2.25(m, 19H),2.30-2.40(m, 1H), 2.55-2.7(m,4H), 3.8-3.9(m, 1H), 2.95(s,3H), 3.1-3.2(m,1H), 3.3-3.4 (m,5H), 3.5-3.6(m,1H), 4.1-4.15(m,1H), 7.1-7.15(m,1H),7.3-7.45(m,2H) ppm.

EXAMPLE 1185(S)-1-Cyclopropylmethyl-5-(3,4-dichlorophenyl)-5-(2-[3-(4-methanesulphonamidopiperidin-1-yl)azetidin-1-yl]ethyl)-2-piperidone

The title compound was prepared by a similar method to that used inExample 117 using the appropriate aminopiperidine starting material (seeExample 112). LRMS m/z=557(m+1)⁺.

¹ H-NMR (CDC₁₃):δ=0.25-0.35(m,2H), 0.5-0.65(m,2H), 0.8-1.1 (m,3H),1.2-1.35 (m,3H), 1.5-1.7(m,3H), 1.8-2.4(m,9H), 2.6-2.8(m,3H),2.85-3.0(m,3H), 3.1-3.2 (m, 1H), 3.25-3.5(m,4H), 3.7-3.8(m,1H),4.15-4.2(m, 1H), 7.1-7.4(m,3H) ppm.

EXAMPLE 1195(S)-5-(2-[3-(4-Carbamoylpiperazin-1-yl)azetidin-1-yl]ethyl)-1-(cyclopropylmethyl)-5-(3,4-dichlorophenyl)-2-piperidone##STR346##

To a solution of the compound of Example 105 (10 mg, 0.2 mmol) indichloromethane (3 ml) at room temperature under nitrogen was addedtrimethylsilylisocyanate (0.032 ml) and the mixture was stirred at roomtemperature for sixteen hours. The solvent was removed under reducedpressure and the product was purified by column chromatography usingsilica gel eluting with dichloromethane:methanol:concentrated ammoniasolution (89:10:1, by volume) to give the title compound (69 mg). TLCRf=0.25 (silica, dichloromethane:methanol:concentrated ammonia solution,89:10:1, by volume). LRMS m/z=508 (m+1)⁺.

¹ H-NMR (CDCl₃):δ=0.25-0.4(m,2H), 0.55-0.7(m,2H), 0.95-1.1(m,1H),1.6-1.9 (m,2H), 1.95-2.4(m, 10H), 2.7-2.75(m,2H), 2.9-2.95(m, 1H),3.1-3.2(m, 1H), 3.35-3.5(m,8H), 3.7-3.8(m,₁₁ H), 4.4(br.s,2H),7.1-7.4(m,3H) ppm.

EXAMPLE 1205(S)-5-(2-[3-(4-Acetamidopiperidin-1-yl)azetidin-1-yl]ethyl)-1-cyclopropylmethyl-5-(3,4-dichlorophenyl)-2-piperidone##STR347##

To a solution of the compound of Example 112 (300 mg, 3.65 mmol) andtriethylamine (255 μl) in dichloromethane (40 ml) under nitrogen at roomtemperature was added acetic anhydride (4 μl) and the reaction wasstirred for eighteen hours. A further portion of acetic anhydride (80μl) was then added and stirring continued for 1 hour. The reaction waswashed with water (2×30 ml) followed by brine (30 ml). The combinedorganic layers were dried using anhydrous magnesium sulphate and thenevaporated under reduced pressure to give a yellow oil. This wasdissolved in ethyl acetate (40 ml) and extracted with 2N aqueoushydrochloric acid solution (2×100 ml). The combined acidic aqueousextracts were basified using saturated aqueous sodium bicarbonatesolution and the aqueous layer extracted using ethyl acetate (2×100 ml).The combined organic layers were dried using anhydrous sodium sulphate.The solvent was removed under reduced pressure to provide the titlecompound (53 mg). TLC Rf=0.1 (silica, methanol:dichloromethane; 1:9, byvolume). LRMS m/z=629 (m)⁺.

¹ H-NMR (CDC₁ ₃):δ=0.2-0.4(m,2H), 0.5-0.7(m,2H), 0.95-1.05(m,1H),1.3-1.4(m,2H), 1.5-1.7(m,1H), 1.75-2.2(m,₁ 3H), 2.3-2.4(m, 1H),2.5-2.7(m,4H), 2.95(t, 1H), 3.05-3.1 (m, 1H), 3.4-3.6(m,4H), 3.8(d,2H),5.2(s, 1H), 7.1 (d, 1H), 7.35-7.4(m,2H) ppm.

EXAMPLES 121 and 122

The compounds of the following tabulated Examples of the generalformula: ##STR348## were prepared by a similar method to that of Example120 using the appropriate piperazine starting material (see Example 105)and the appropriate acylating agent.

    __________________________________________________________________________    Ex.                LRMS                                                       No. --X.sup.1 --R.sup.2                                                                       m.p.                                                                             m/z Analysis/.sup.1 H-NMR                                  __________________________________________________________________________    121.sup.1,2                                                                       8 #STR349## -- --  .sup.1 H-NMR(CDCl.sub.3): δ = 0.25-0.4(m,2H),                            0.5-0.7 (m,2H), 1.0-1.1(m,1H), 1.5-1.7(m,2H),                                1.7-1.9 (m,1H), 1.95-2.4(m,12H), 2.6-2.8(m,2H),                               2.8- 2.95(m,1H), 3.1-3.2(m,1H), 3.3-3.5(m,6H),                                3.5- 3.65(m,2H), 3.7-3.8(m,1H), 7.1(d,1H), 7.35-                              7.45(m,2H) ppm.                                        122.sup.1,3                                                                       9 #STR350## -- --  .sup.1 H-NMR(CDCl.sub.3): δ = 0.2-0.4(m,2H),                            0.5-0.7 (m,2H), 1.0-1.1(m,1H), 1.5-1.7(m,2H),                                 1.7-1.9 (m,1H), 1.95-2.4(m,9H), 2.65(q,2H),                                   2.85-3.0 (m,1H), 3.1-3.2(m,1H), 3.25-3.5(m,4H),                               3.5-3.8 (m,5H), 7.1(d,1H), 7.35-7.4(m,2H)              __________________________________________________________________________                           ppm.                                                    Footnotes:                                                                    .sup.1 Purified by column chromatography using silica gel eluting with        dichloromethane:methanol (90:10, by volume).                                  .sup.2 Acetyl chloride was used as the acylating agent.                       .sup.3 Trifluoroacetic anhydride was used as the acylating agent.        

EXAMPLE 1235(S)-5-(2-[3-(4-Aminosulphonylpiperazin-1-yl)azetidin-1-yl]ethyl)-1-cyclopropylmethyl-5-(3,4-dichlorophenyl)-2-piperidone##STR351## (a)4(S)-4-Cyano-4-(3,4-dichlorophenyl)-5-(1,3-dioxolan-2-yl)pentan-1-oicacid

To a 1.0M solution of lithium hexamethyldisilylazide in tetrahydrofuran(4.691) at 5° C. under nitrogen was added a solution of3,4-dichlorophenylacetonitrile (750 g, 4.28 moles) in tetrahydrofuran(750 ml), dropwise, over 45 minutes. The reaction was allowed to stirfor 2 hours. The reaction was cooled again to 5° C. and a solution of2-bromomethyl-1,3-dioxolane (782 g) in tetrahydrofuran (780 ml) added,dropwise, over fifty minutes. Tetra-n-butylammonium iodide (75 g) wasadded, portionwise, and the mixture allowed to warm to room temperatureand stirred for 14 hours. The reaction was then cooled to 5° C. and a1.0M solution of lithium hexamethyidisilylazide in tetrahydrofuran (4.69l) was added, dropwise. The mixture was stirred for 5 hours at roomtemperature. The solution was cooled to 5° C. and a solution of ethyl3-bromopropanoate (840.5 g) in tetrahydrofuran (840 ml) was added,dropwise, over 50 minutes. The reaction was allowed to stir for 14hours. The reaction mixture was cooled to 5° C. and 1.5M aqueous sodiumhydroxide solution (containing 255 g of sodium hydroxide) was added andthe mixture stirred for 14 hours. Water (5l) was added and the mixturewas extracted with ethyl acetate (2×3 l). The combined organic extractswere washed with water (2×5 l). The aqueous phases were combined andacidified to pH1 using 5N aqueous hydrochloric acid solution and thenextracted with ethyl acetate (2×3 l). The combined organic extracts wereconcentrated under reduced pressure to a concentration of approximately3 ml/g based on the theoretical yield of the product.

The above experimental procedure was then repeated on an identicalscale. To the combined organic solutions from both reactions was added(S)-(-)-alpha-methylbenzylamine (1.13 kg) and the mixture stirred for 14hours. The thick slurry was then stirred with cooling in an ice-bath for2 hours, filtered, the solid washed with ethyl acetate (2×1 l) and thendried under reduced pressure at 35° C. to give 1.85 kg of material. Aportion of this material (1.34 kg) was dissolved in a mixture ofbutanone (2 l) and water (503 ml) that was heated under reflux. Afurther portion of butanone (4.7 l) was added and the solution wasallowed to cool slowly to room temperature overnight. The resultingsolid was filtered off (the filtrate was used in Preparation 192),washed with butanone (2×1 l) and ried under reduced pressure at 35° C.for 10 hours to give 563 g of material (93.8% e.e.). A furtherrecrystallisation from butanone/water gave the title compound as a(S)-(-)-alpha-methylbenzylamine salt in 99.8% e.e. To a stirred solutionof this salt in ethyl acetate and water was added 5N aqueoushydrochloric acid solution until pH1 was achieved. The mixture wasstirred for a further 30 minutes, the layers separated and the aqueousphase extracted with ethyl acetate. The combined organic layers werewashed with water and the solvent removed by evaporation under reducedpressure to give the title compound.

¹ H-NMR (CDCl₃):δ=2.05-2.35(m,4H), 2.4-2.65(m,2H), 3.7-4.0(m,4H),4.75-4.85(m, 1H), 7.25-7.55(m,3H), 9.9(s,br., 1H,acid) ppm.

(b)5(S)-5-(3,4-Dichlorophenyl)-5-(1,3-dioxolan-2-ylmethyl)-2(1H)-piperidone

To a solution of the compound of Example 123(a) (13.5 g, 39.22 mmol) inglacial acetic acid (130 ml) was added platinum oxide (1.21 g) and themixture stirred under an atmosphere of hydrogen at 414 kPa (60 psi) andat room temperature for 17 hours. The catalyst was removed by filtrationand a further portion of platinum oxide (1.21 g) added. The reactionmixture was then stirred under an atmosphere of hydrogen 414 kPa (60psi) and at room temperature for 48 hours. The catalyst was removed byfiltration and the solution concentrated under reduced pressure. Theresidue was dissolved in ethyl acetate (80 ml) and washed with saturatedaqueous sodium bicarbonate solution (2×75 ml). The organic phase wasthen separated and the solvent removed under reduced pressure. Theresulting solid was stirred in a solution of hexane (20 ml) and ethylacetate (20 ml) for 2 hours at 0° C. and then filtered off to give thetitle compound (8.15 g).

¹ H-NMR (CDCl₃):δ=1.85-1.95(m,1H), 2.0-2.25(m,4H), 2.35-2.4(m,1H),3.45-3.55(m, 1H), 3.65-3.75(m,2H), 3.8-3.9(m,3H), 4.35-4.4(m, 1H),6.15(s,br., 1H), 7.2-7.45(m,3H) ppm.

(c)5(S)-1-Cyclopropylmethyl-5-(3,4-dichlorophenyl)-5-(1,3-dioxolan-2-ylmethyl)-2-piperidone

To a solution of the compound of Example 123(b) (38.6 g, 117 mmol) indimethyl sulphoxide (190 ml) was added potassium hydroxide (19.7 g) andthe mixture stirred at room temperature for 20 minutes.Bromomethylcyclopropane (17.37 g) was then added over 20 minutes and thereaction stirred for a further 140 minutes. The reaction was poured intoa mixture of ice (10 g) and water (900 ml) and the mixture extractedwith dichloromethane (2×400 ml). The combined organic layers were washedwith water (400 ml) and the solvent removed under reduced pressure togive the title compound (45.4 g).

¹ H-NMR (CDCl₃):δ=0.3-0.4(m,2H), 0.55-0.65(m,2H), 1.05-1.15(m,1H),1.9-1.95(m, 1H), 2.0-2.25(m,4H), 2.35-2.45(m, 1H), 3.15-3.2(m, 1H),3.5-3.55(m,2H), 3.65-3.75(m,2H), 3.9-4.0(m,3H), 4.35-4.4(m, 1H),7.2-7.5(m,3H) ppm.

(d)5(S)-1-Cyclopropylmethyl-5-(3,4-dichlorophenyl)-5-formylmethyl-2-piperidon

To a solution of the compound of Example 123(c) (73.16 g, 190 mmol) intetrahydrofuran (730 ml) at 5° C. was added 5N aqueous hydrochloric acidsolution (730 ml) over 20 minutes. The reaction mixture was stirred atroom temperature for 17 hours. The tetrahydrofuran was removed underreduced pressure, the residue diluted with water (200 ml) and extractedwith ethyl acetate (2×500 ml). The combined organic layers were thenwashed with water (500 ml) and the solvent removed under reducedpressure to give the title compound (62.1 g).

¹ H-NMR (CDC₁ ₃):δ=0.25-0.35(m,2H), 0.55-0.65(m,2H), 1.05-1.1(m,1H),2.15-2.25(m,3H), 2.35-2.5(m,1H), 2.65-2.75(m,1H), 2.95-3.05(m,1H),3.15-3.2(m,1H), 3.45-3.6(m,2H), 3.95-4.0(m, 1H), 7.2-7.45(m,3H), 9.5(s,1H) ppm.

(e) 1-Aminosulphonyl-4-benzylpiperazine

A solution of 1-benzylpiperazine (5 g, 28.4 mmol) and sulphamide (2.77g) in 1,4-dioxane (25 ml) was heated under reflux for 24 hours. Thesolution was cooled and poured into water (100 ml). The solid wasfiltered off, washed with toluene (100 ml) and dried under reducedpressure to give the title compound (4.75 g).

¹ H-NMR (d₆ -DMSO):δ=2.41-2.5(m,4H), 2.95-3.0(m,4H), 3.5(s,2H),6.75(s,2H), 7.25-7.35(m,5H) ppm.

(f) 1-Aminosulphonylpiperazine

A mixture of the compound of Example 123(e) (20 g, 78.3 mmol) and 10%w/w palladium-on-carbon (4 g) in ethanol (140 ml) was stirred under anatmosphere of hydrogen at 345 kPa (50 psi) and at 50° C. for 23 hours.The catalyst was removed by filtration and washed with ethanol (100 ml).

The filtrate was concentrated under reduced pressure to approximately 40ml in volume and the slurry kept at 0-5° C. for 12 hours. The solid wasfiltered off to give a first crop of the title compound (2 g). Thecatalyst separated earlier was heated under reflux in ethanol (150 ml).The mixture was filtered whilst hot and the pad washed with ethanol (50ml). The solvent was removed under reduced pressure. The solid wasslurried with acetone (100 ml) and filtered off to give a second crop ofthe title compound (8 g).

¹ H-NMR (d₆ -DMSO):δ=2.3-2.9(m,9H), 6.65(s,br.,1H) ppm.

(g) 1-Aminosulphonyl-4-(1-diphenylmethylazetidin-3-yl)piperazine

A solution of 1-diphenylmethyl-3-methanesulphonyloxyazetidine (seePreparation 54) (4.8 g, 15.1 mmol) and 1-aminosulphonylpiperazine (seeExample 123(f)) (5 g) in acetonitrile (50 ml) was heated under refluxfor 4 hours. The reaction was cooled and the solid filtered off andwashed with acetonitrile (50 ml). The filtrate was concentrated underreduced pressure and the residue slurried in hot toluene (50 ml),cooled, the solid filtered off and washed with toluene (50 ml). Theproduct was then further purified by slurrying in hot ethyl acetate (3ml), cooling and filtering to give the title compound (0.47 g).

¹ H-NMR (d₆ -DMSO):δ=2.25-2.3(m,4H), 2.7-2.75(m,2H), 2.85-2.95(m,3H),3.05-3.1 (m,2H), 3.2-3.25(m,2H), 4.4(m, 1H), 6.7(m,2H), 7.15-7.4(m, 10H)ppm.

(h) 1-Aminosulphonyl-4-(azetidin-3-yl)piperazine dihydrochloride

To a solution of the compound of Example 123(g) (5 g) in methanol (50ml) was added 10% aqueous hydrochloric acid solution (9.4 ml) andPearlman's catalyst (20% w/w Pd(OH)-on-carbon) (0.6 g). The mixture wasshaken under an atmosphere of hydrogen using a Parr shaker for 14 hours.

After this time the catalyst was removed by filtration, the filtratereturned to the Parr shaker and a further 0.6 g of Pearlman's catalystadded. The reaction was shaken under an atmosphere of hydrogen for 14hours. The catalyst was removed by filtration and washed with water (100ml). The filtrate was concentrated under reduced pressure. The residuewas stirred in acetonitrile (50 ml) for 1 hour and the mixture left tostand for 14 hours. The solid was filtered off and dried under reducedpressure to give the title compound (3.28 g).

¹ H-NMR (d₆ -DMSO):δ=2.35-2.45(m,5H), 2.9-3.0(m,4H), 3.25-3.35(m,1H),3.75-3.9(m,4H), 6.8(s,br.,2H) ppm.

(i)5(S)-5-(2-[3-(4-Aminosuphonylpiperazin-1-yl)azetidin-1-yl]ethyl)-1-cyclopropylmethyl-5-(3,4-dichlorophenyl)-2-piperidoneTo a solution of the compound of Example 123(h) (18.97 g) intetrahydrofuran (140 ml) at room temperature was added triethylamine (18ml) and the mixture stirred for 30 minutes. A solution of the compoundof Example 123(d) (20 g) in tetrahydrofuran (60 ml) was then added.After 2 hours, the solution was cooled to 2° C. and sodiumtriacetoxyborohydride (17.44 g) was added, portionwise, followed byacetic acid (3.37 ml) and the reaction was allowed to warm to roomtemperature and stirred for 2 hours. The reaction was poured into water(50 ml) and a 10% w/w aqueous sodium bicarbonate solution was addeduntil pH9 was achieved. Ethyl acetate (200 ml) was added and the layersseparated. The aqueous phase was extracted with ethyl acetate (50 ml),the combined organic extracts were washed with a 10% w/w aqueous sodiumbicarbonate solution (100 ml) and the solvent was removed under reducedpressure to give the title compound (28.27 g).

¹ H-NMR--as for the compound of Example 32.

Pharmacological Data

A representative selection of the compounds of the Examples were testedin vitro for their affinity to the human NK₂ receptor by testing theirability to compete with [¹²⁵ I] NKA for binding to membranes preparedfrom Chinese hamster ovary cells expressing the cloned human NK₂receptor (Method A) and for their ability to antagonise the contractileeffects of [βAla⁸ ] NKA.sub.(4-10) in the rabbit pulmonary artery(Method B) by the methods described on pages 40 and 41 of thespecification.

The results are tabulated below:

    ______________________________________                                                         METHOD A  METHOD B                                           EXAMPLE NO.      (pIC.sub.50)                                                                            (pA.sub.2)                                         ______________________________________                                        14               7.2       7.9                                                31               9.0       8.3                                                73               9.5       8.9                                                75               8.3       9.1                                                (enantiomeric pair A)                                                         89               8.2       8.6                                                104              8.8       9.2                                                ______________________________________                                    

The following Preparations illustrate the preparation of certainstarting materials used in the syntheses of the compounds of thepreceding Examples.

Preparation 12-(3,4-Dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butanenitrile

To a mixture of 60% w/w sodium hydride dispersion in oil (19.24 g, 1.05mol. equiv.) in dry tetrahydrofuran (450 ml) at 0° C. under nitrogen wasadded a solution of 3,4-dichlorophenylacetonitrile (89.5 g, 1 mol.equiv.) in dry tetrahydrofuran (450 ml), dropwise over forty minutes.After a further thirty minutes, a solution of2-bromoethoxytetrahydropyran (100 g , 1 mol. equiv.) in tetrahydrofuran(100 ml) was added and the mixture allowed to warm to room temperatureand stirred for fourteen hours. 30% Aqueous ammonium chloride solution(500 ml) was added and the mixture extracted with diethyl ether (2×400ml). The organic layers were combined and washed with water (2×400 ml),dried over magnesium sulphate, and the solvent removed under reducedpressure. The residue was then chromatographed using silica gel elutingwith a solvent gradient of diethyl ether:hexane (1:9 to 1:1, by volume)to give the title compound (51 g). TLC R_(f) =0.55 (silica, methyltert-butyl ether:hexane, 1:1, by volume). LRMS m/z=333 (m+NH₄)⁺.

¹ H-NMR (CDCl₃):δ=1.5-1.9 (m,6H), 2.05-2.3 (m,2H), 2.4-2.65 (m,2H),2.8-2.95 (m,2H), 4.0-4.1 (m,1H), 4.5-4.6 (m,1H), 7.2-7.25 (m,1H),7.25-7.5 (m,2H), ppm.

Preparation 2 Ethyl4-cyano-4-(3,4-dichlorophenyl)-6-(tetrahydropyran-2-yloxy)hexanoate

To a solution of diisopropylamine (15 ml, 0.77 mol. equiv.) intetrahydrofuran (80 ml) at -78° C. under nitrogen was addedn-butyllithium (77.3 ml of a 2.5 M solution in hexane, 1.4 mol. equiv.)and the solution was then allowed to warm to room temperature over twohours. The solution was cooled to -78° C. and a solution of the compoundof Preparation 1 (43.9 g, 138 mmol) in tetrahydrofuran (180 ml) wasadded slowly. The resulting solution was allowed to warm to roomtemperature slowly over two hours. The solution was then cooled to -78°C. and a solution of ethyl 3-bromopropanoate (22.36 ml, 1.3 mol. equiv.)in tetrahydrofuran (70 ml) added dropwise. Tetra-n-butylammonium iodide(50 g, 1 mol. equiv.) was then added, the reaction allowed to warm toroom temperature and stirred for fourteen hours. Water (10 ml) was thenadded and the solution concentrated under reduced pressure. Water (400ml) and brine (400 ml) were added and the mixture extracted with ethylacetate (2×500 ml). The combined organic layers were washed with water(2×300 ml), dried over magnesium sulphate, and the solvent removed underreduced pressure. Chromatography using silica gel eluting with diethylether:hexane (1:1, by volume) gave the title compound (35 g).TLC R_(f)=0.30 (silica, diethyl ether:hexane, 1:1, by volume).

¹ H-NMR (CDCl₃):67 =1.25 (t,3H), 1.35-1.8 (m,6H), 2.0-2.55 (m,6H),3.3-3.45 (m,2H), 3.65-3.8 (m,2H), 4.0-4.1 (m,2H), 4.4-4.5 (m,1H),7.2-7.55 (m,3H) ppm.

Preparation 35-(3,4-Dichlorophenyl)-5-(2-[tetrahydropyran-2-yloxy]ethyl)-2(1H)-piperidon

The compound of Preparation 2 (18.7 g, 45.2 mmol) was dissolved insaturated ammoniacal ethanol solution (500 ml) which contained Raneynickel (3.5 g). The mixture was stirred under hydrogen at atmosphericpressure for seven hours. The catalyst was then removed by filtration,the ethanol removed under reduced pressure and the residuechromatographed using silica gel eluting initially with diethyl etherand then with methanol:dichloromethane (1:9, by volume) to give thetitle compound (10.4 g). TLC R_(f) =0.45 (silica,methanol:dichloromethane, 1:9, by volume). LRMS m/z=372(m+1)⁺.

¹ H-NMR (CDCl₃):δ=1.4-1.8 (m,6H), 1.9-2.1 (m,5H), 2.3-2.45 (m,1H),3.0-3.2 (m,1H), 3.0-3.2 (m,1H), 3.35-3.85 (m,4H), 4.35-4.4 (m,1H), 6.05(s,br.,1H), 7.15-7.45 (m,3H) ppm.

Preparation 4 5-(3,4-Dichlorophenyl)-5-(2-hydroxyethyl)-2(1H)-piperidone

To a saturated solution of hydrogen chloride in methanol (350 ml) atroom temperature was added the compound of Preparation 3 (10.4 g, 28mmol). Hydrogen chloride gas was then bubbled through the solution withstirring for forty minutes and the reaction then left to stir at roomtemperature for fourteen hours. The solvent was removed under reducedpressure. Saturated aqueous sodium bicarbonate solution (300 ml) wasadded and the aqueous phase extracted with ethyl acetate (4×300 ml). Thecombined organic layers were dried over magnesium sulphate, filtered,and the solvent removed under reduced pressure to give a white solid.This was crystallised from ethyl acetate to give the title compound (5.5g). TLC R_(f) =0.23 (silica, methanol: dichloromethane, 1:9, by volume).m.p. 167-168° C. LRMS m/z=288(m+1)⁺. Found: C, 54.02; H, 5.03; N, 4.52.C₁₃ H₁₅ Cl₂ NO₂ requires C, 54.18; H, 5.25; N, 4.84%.

¹ H-NMR (d₆ -DMSO):δ=1.7-2.2 (m,6H), 3.1-3.15 (m,2H), 3.25-3.3 (m,1H),3.6-3.7 (m,1H), 4.3-4.35 (m,1H), 7.35-7.65 (m,4H) ppm.

Preparation 55-(3,4-Dichlorophenyl)-5-(2-methanesulphonyloxyethyl)-2(1H)-piperidone

To a solution of the compound of Preparation 4 (5.44 g, 18.9 mmol) indry dichloromethane (100 ml) was added triethylamine (3.95 ml, 1.5 mol.equiv.) and the solution cooled to 0° C. Methanesulphonyl chloride (1.9ml, 1.3 mol. equiv.) was then added and the reaction allowed to warm toroom temperature and stirred for 2.5 hours. The reaction was washed withwater (3×200 ml), dried over magnesium sulphate, filtered and thesolvent removed under reduced pressure to give the title compound (7.1g). TLC R_(f) =0.24 (silica, methanol:dichloromethane, 1:19, by volume).

¹ H-NMR (CDCl₃):δ=2.0-2.5 (m,6H), 2.9 (s,3H), 3.45-4.1 (m,4H), 6.7(s,br.,1H), 7.2-7.5 (m,3H) ppm.

Preparation 6 5-(3,4-Dichlorophenyl)-5-formylmethyl-2(1H)-piperidone

To a solution of oxalyl chloride (1.6 ml, 1.1 mol.equiv.) in drydichloromethane (200 ml) at -78° C. was added dry dimethylsulphoxide(3.0 ml, 2.4 mol. equiv.), dropwise, and the solution allowed to stirfor one hour. A solution of the compound of Preparation 4 (5 g) in amixture of dichloromethane (100 ml) and dry dimethylsulphoxide (10 ml)was then added, dropwise over fifteen minutes, and the mixture allowedto stir at -78° C. for one hour. Triethylamine (12 ml, 5 mol. equiv.)was then added and the mixture allowed to warm to room temperature overfour hours. Water (25 ml) was added and the mixture extracted withdichloromethane (3×100 ml). The combined organic layers were dried overmagnesium sulphate, filtered and the solvent removed under reducedpressure to give a gum which was chromatographed using silica geleluting with a solvent gradient of methanol:dichloromethane (1:49 to1:5, by volume) to give the title compound (1.09 g).

¹ H-NMR (CDCl₃):δ=2.05-2.2 (m,2H), 2.35-2.5 (m,1H), 2.7-2.75 (m,1H),2.95-3.0 (m,1H), 3.45-3.6 (m,2H), 3.85-3.9 (m,1H), 6.0 (s,br.,1H),7.2-7.45 (m,3H), 9.5 (m,1H) ppm.

Preparation 75-(3,4-Dichlorophenyl)-1-(4-phenylbenzyl)-5-(2-[tetrahydropyran-2-oxy]ethyl)-2-piperidone

To a solution of the compound of Preparation 3 (500 mg, 1.34 mmol) indry dimethylformamide (10 ml) at room temperature under nitrogen wasadded 60% w/w sodium hydride dispersion in oil (54 mg, 1.05 mol. equiv.)and the mixture allowed to stir at room temperature for one hour. Asolution of 4-phenylbenzyl bromide (365 mg, 1.1 mol. equiv.) indimethylformamide (1 ml) was then added dropwise and the mixture allowedto stir at room temperature for two hours. Water (2 ml) was then addedfollowed by saturated aqueous sodium bicarbonate solution (10 ml) andsaturated ammonium chloride solution (10 ml). The mixture was thenextracted with ethyl acetate (3×50 ml) and the combined organic layerswere washed with saturated aqueous ammonium chloride solution (2×50 ml).The organic phase was dried over magnesium sulphate, filtered, and thesolvent removed under reduced pressure to give a white foam. This crudeproduct was then chromatographed using silica gel eluting with ethylacetate to give the title compound (456 mg). TLC Rf=0.47 (silica, ethylacetate).

¹ H-NMR (CDCl₃):δ=1.5-1.8 (m,6H), 1.8-2.05 (m,2H), 2.05-2.2 (m,3H),2.4-2.55 (m,1H), 2.85-3.1 (m,1H), 3.3-3.75 (m,4H), 3.75-3.85 (m,1H),4.2-4.4 (m,2H), 5.0-5.1 (d,1H), 6.8-6.9 (t,1H), 7.05-7.1 (d,1H), 7.2-7.3(m,1H), 7.3-7.5 (m,5H), 7.55-7.65 (m,4H) ppm.

Preparation 85-(4-Chlorophenyl)-1-(cyclohexyimethyl)-5-(2-hydroxyethyl)-2-piperidone

To a methanolic solution (20 ml) of the compound of Preparation 51 (1 g,1 mol. equiv.) was added Amberlyst H-15 (trade mark) ion exchange resin(0.33 g, 0.33 w/w equiv.) and the reaction stirred for twenty hours atroom temperature. The resin was removed by filtration and the methanolremoved from the filtrate under reduced pressure. The residue wasdissolved in ethyl acetate (20 ml) and the mixture washed with water (5ml) and brine (5 ml). The organic layer was dried using anhydrousmagnesium sulphate, filtered and the filtrate evaporated to drynessunder reduced pressure to give the title compound as a white solid (0.81g) which was used without further purification. TLC R_(f) =0.7 (silica,methanol: dichloromethane, 1:9 by volume). LRMS m/z=350(m+1)⁺.

Preparation 9 Ethyl 4,4-difluorocyclohexanecarboxylate

To a solution of diethylaminosulphur trifluoride (7.76 ml, 2 mol.equiv.) in carbon tetrachloride (75 ml) at 0° C. was added ethyl4-oxocyclohexanecarboxylate (5 g, 29.4 mmol), dropwise, and the mixturewas allowed to stir at room temperature for fourteen hours.

Water (50 ml) was then added carefully. The organic phase was washedwith water (3×50 ml), dried over anhydrous magnesium sulphate, filteredand the solvent removed under reduced pressure to give the titlecompound as a yellow oil (1.96 g) which was purified by distillation.

¹ H-NMR (CDCl₃):δ=1.2-1.3 (t,3H), 1.65-1.9 (m,4H), 1.95-2.2 (m,3H),2.2-2.45 (m,2H), 4.05-4.2 (q,2H) ppm.

Preparation 10 4,4-Difluorocyclohexylmethanol

To a stirred suspension of lithium aluminium hydride (350 mg) in drydiethyl ether (30 ml) at 0° C. under nitrogen was added a solution ofthe compound of Preparation 9 (1.96 g) in dry diethyl ether (15 ml),dropwise. The mixture was then allowed to stir for one hour. Water (0.5ml) was then added followed by 2N aqueous sodium hydroxide solution (0.5ml) and then water (0.5 ml). The inorganic solids were removed byfiltration and the filtrate concentrated under reduced pressure to givethe title compound as a colourless oil (1.59 g).

¹ H-NMR (CDCl₃):δ=1.15-1.4 (m,2H), 1.4-1.5 (m,2H), 1.5-1.7 (m,1H),1.7-2.0 (m,3H), 2.0-2.3 (m,2H), 3.45-3.6 (m,2H) ppm.

Preparation 11 4,4-Difluoro-1-(4-methylphenylsulphonyloxymethyl)cyclohexane

To a solution of the compound of Preparation 10 (500 mg, 3.33 mmol) indichloromethane (10 ml) at room temperature was added triethylamine(0.62 ml, 1.5 mol. equiv.) followed by p-toluenesulphonyl chloride (570mg, 1 mol. equiv.) and the reaction mixture allowed to stir for fourteenhours. Water (25 ml) was then added, the layers separated, the organicphase further washed with water (2×25 ml) and the organic layer driedover anhydrous magnesium sulphate. The solution was filtered and thesolvent removed under reduced pressure. The crude product was thenpassed through a short pad of silica eluting with diethyl ether:hexane(1:4, by volume). The solvent was removed from the eluted fraction underreduced pressure and the product crystallised by trituration usinghexane to give the title compound as a white solid (100 mg).

¹ H-NMR (CDCl₃):δ=1.2-1.35 (m,2H), 1.55-1.7 (m,1H), 1.7-1.85 (m,4H),2.0-2.15 (m,2H), 2.45-2.5 (s,3H), 3.85-3.9 (d,2H), 7.3-7.4 (d,2H),7.75-8.0 (d,2H) ppm.

Preparation 125-(3,4-Dichlorophenyl)-1-(4,4-difluorocyclohexylmethyl)-5-(2-[tetrahydropyran-2-oxy]ethyl)-2-piperidone

To a solution of the compound of Preparation 3 (121 mg, 0.33 mmol) indry dimethylformamide (3 ml) under nitrogen was added 60% w/w sodiumhydride dispersion in oil (14 mg) and the mixture was allowed to stir atroom temperature for forty-five minutes. To this mixture was added thecompound of Preparation 10 (99 mg, 1 mol. equiv.) and the mixture heatedat 50° C. for five hours. To effect a more complete reaction a furtherportion of 60% w/w sodium hydride dispersion in oil (7 mg, 0.5 mol.equiv.) was added and the reaction heated at 50° C. for a further threehours. Water (1 ml) was then added and the mixture evaporated to drynessunder reduced pressure. The residue was then dissolved in ethyl acetate(20 ml) and the organic phase washed with water (2×20 ml). The organicphase was then dried over anhydrous magnesium sulphate, filtered and thesolvent removed under reduced pressure to give a gum. This was purifiedby column chromatography using silica gel eluting with a solventgradient of dichloromethane:methanol (100:0 to 9:1, by volume) to givethe title compound (80 mg). LRMS m/z=506(m+1)⁺.

¹ H-NMR (CDCl₃):δ=1.15-1.6 (m,8H), 1.6-1.9 (m,5H), 1.9-2.3 (m,7H),2.4-2.5 (m,1H), 3.0-3.3 (m,2H), 3.3-3.6 (m,4H), 3.6-3.8 (m,2H), 4.3-4.4(m,1H), 7.05-7.15 (d,1H), 7.3-7.4 (s,1H), 7.4-7.45 (d,1H) ppm.

Preparation 13 Methanesulphonyloxymethylcycloheptane

To a solution of cycloheptylmethanol (1.0 g, 7.81 mmol) indichloromethane (20 ml) at 0° C. under nitrogen was added triethylamine(1.63 ml, 1.5 mol. equiv.) Methanesulphonyl chloride (0.73 ml, 1.2 mol.equiv.) was added, dropwise, and the reaction allowed to stir for twohours at room temperature. Water (50 ml) and dichloromethane (50 ml)were added. The organic phase was separated, washed with water (2×50 ml)and then dried over anhydrous magnesium sulphate. The solution was thenfiltered and the solvent removed under reduced pressure to give thetitle compound as an oil (1.66 g).

¹ H-NMR (CDCl₃):δ=1.15-1.3 (m,2H), 1.4-1.6 (m,6H), 1.6-1.8 (m,4H),1.85-2.0 (m,1H), 2.95-3.0 (s,3H), 3.95-4.05 (d,2H) ppm.

Preparations 14 to 16

The compounds of the following tabulated Preparations of the generalformula: ##STR352## were prepared by a similar method to that used inPreparation 1 using the appropriate acetonitrile derivative startingmaterials.

    __________________________________________________________________________    Prep.      LRMS                                                               No.                                                                              R.sup.1 m/z   Analysis/.sup.1 H-NMR                                        __________________________________________________________________________    14                                                                               0 #STR353##                                                                           --    .sup.1 H-NMR(CDCl.sub.3): δ = 1.5-1.9(m,6H),                            2.05-2.3(m,2H), 3.4- 4.1(m,5H), 4.55-4.65(m,1H),                              7.05-7.3(m,3H) ppm.                                          15                                                                               1 #STR354##                                                                           297 (m + NH.sub.4).sup.+                                                            .sup.1 H-NMR(CDCl.sub.3): δ = 1.5-1.7(m,4H),                            1.7-1.9(m,2H), 2.05- 2.3(m,2H), 3.45-3.6(m,2H),                               3.8-4.1(m,3H), 4.6-4.65 (m,1H), 7.25-7.4(m,4H) ppm.          16                                                                               2 #STR355##                                                                           297 (m + NH.sub.4).sup.+                                                            .sup.1 H-NMR(CDCl.sub.3): δ = 1.5-1.85(m,6H),                           2.05-2.2(m,2H), 3.45-3.6(m,2H), 3.8-3.95(m,2H),                               4.05-4.1(m,1H), 4.55- 4.65(m,1H), 7.3-7.4(m,4H)              __________________________________________________________________________                     ppm.                                                     

Preparations 17 to 19

The compounds of the following tabulated Preparations of the generalformula: ##STR356## were prepared by a similar method so that used inPreparation 2 using the appropriate butanenitrile derivative startingmaterials (see Preparations 14 to 16).

    __________________________________________________________________________    Prep.      LRMS                                                               No.                                                                              R.sup.1 m/z   Analysis/.sup.1 H-NMR                                        __________________________________________________________________________    17                                                                               0 #STR357##                                                                           --    Found: C, 62.80; H, 6.42; N, 3.85. C.sub.20 H.sub.25                          NO.sub.4 F.sub.2 requires C, 62.98; H, 6.61; N, 3.67%.                        .sup.1 H-NMR(CDCl.sub.3): δ = 1.2-1.3(m,3H),                            1.4-1.8(m,6H), 2.05- 2.55(m,6H), 3.3-3.5(m,2H),                               3.65-3.85(m,2H), 4.05-4.15 (m,2H), 4.4-4.5(m,1H),                             7.15-7.3(m,3H) ppm.                                          18                                                                               1 #STR358##                                                                           397 (m + NH.sub.4).sup.+                                                            .sup.1 H-NMR(CDCl.sub.3): δ = 1.2-1.3(m,5H),                            1.4-1.8(m,6H), 2.05- 2.55(m,6H), 3.35-3.5(m,1H),                              3.65-3.8(m,1H), 4.0-4.1 (m,2H), 7.3-7.45(m,4H) ppm.          19                                                                               2 #STR359##                                                                           397 (m + NH.sub.4).sup.+                                                            .sup.1 H-NMR(CDCl.sub.3): δ = 1.2-1.75(m,10H),                          2.05-2.55(m,5H), 3.25-3.45(m,2H), 3.6-3.85(m,2H),                             3.95-4.1(m,2H), 4.45- 4.5(m,1H), 7.4(s,4H)                   __________________________________________________________________________                     ppm.                                                     

Preparations 20 to 22

The compounds of the following tabulated Preparations of the generalformula: ##STR360## were prepared by a similar procedure to that used inPreparation 3 using the appropriate butanoate derivative startingmaterials (see Preparations 17 to 19).

    __________________________________________________________________________    Prep.      LRMS                                                               No.                                                                              R.sup.1 m/z  Analysis/.sup.1 H-NMR                                         __________________________________________________________________________    20.sup.1                                                                         0 #STR361##                                                                           340 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 1.45-1.75(m,5H),                          1.85-2.15(m,5H), 2.35-2.45(m,1H),3.0-3.15(m,1H),                              3.35-3.55(m,4H), 3.65-3.8(m,2H), 4.35-4.4(m,1H),                              5.95(br.s,1H), 7.05-7.2 (m,3H) ppm.                           21.sup.2                                                                         1 #STR362##                                                                           338 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 1.4-1.8(m,6H),                            1.9-2.0(m,1H), 2.05- 2.25(m,4H), 2.3-2.4(m,1H),                               3.0-3.2(m,1H), 3.4-3.6 (m,3H), 3.65-3.85(m,2H),                               4.3-4.4(m,1H), 6.2(br.s,1H), 7.15-7.3(m,4H) ppm.              22.sup.1                                                                         2 #STR363##                                                                           338 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 1.4-1.8(m,6H),                            1.9-2.45(m,6H), 3.0- 3.1(m,1H), 3.35-3.85(m,5H),                              4.35-4.4(m,1H), 6.05 (br.s,1H), 7.25-7.35(m,4H)               __________________________________________________________________________                    ppm.                                                           Footnotes                                                                     1. Reaction carried out at about 414 kPa (60 psi) and 50° C.           2. Reaction carried out at 50° C.                                 

Preparations 23 to 32

The compounds of the following tabulated Preparations of the generalformula: ##STR364## were prepared by a similar method to that ofPreparation 4 using the appropriate tetrahydropyran derivative startingmaterials (see Preparations 7, 12,44 to 50 and 52).

    __________________________________________________________________________    Prep.                 LRMS                                                    No.                                                                              R         R.sup.1  m/z  Analysis/.sup.1 H-NMR                              __________________________________________________________________________    23                                                                               1 #STR365##                                                                             5 #STR366##                                                                            352 (m + 1).sup.+                                                                  Found: C, 69.16; H, 6.14; N, 3.92. C.sub.20                                   H.sub.21 NF.sub.2 O.sub.2 requires C, 69.55;                                  H, 6.13; N, 4.06%. .sup.1 H-NMR(CDCl.sub.3):                                  δ = 1.75-1.95(m,2H), 2.0-2.25(m,4H),                                    2.45-2.5(m,1H), 3.2-3.4 (m,3H),                                               3.65-3.7(m,1H), 4.4(d,1H), 4.85 (d,1H),                                       6.7-6.85(m,2H), 6.9-7.05(m,1H), 7.3-7.4(m,5H)                                 ppm.                                               24                                                                               1 #STR367##                                                                             6 #STR368##                                                                            344 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 1.75-2.25(m                               ,6H), 2.45-2.5(m,1H), 3.2-3.4(m,3H), 3.65-3.7                                 (m,1H), 4.45(d,1H), 4.75(d,1H), 6.9-7.4 (m,9H)                                ppm.                                               25                                                                               1 #STR369##                                                                             3 #STR370##                                                                            344 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 1.75-1.85(m                               ,1H), 1.9-2.25(m,5H), 2.4-2.5(m,1H), 3.2-3.4                                  (m,3H), 3.65-3.7(m,1H), 4.45(d,1H), 4.8                                       (d,1H),, 6.9-7.4(m,9H) ppm.                        26                                                                               2 #STR371##                                                                             5 #STR372##                                                                            352 (m + 1).sup.+                                                                  .sup.1 H-NMR(d.sub.6 -DMSO): δ =                                        0.8-0.9(m,2H), 1.0-1.25(m,2H), 1.4-1.8(m,6H),                                 1.85- 2.05(m,3H), 2.1-2.3(m,2H), 3.0-3.3                                      (m,6H), 3.35-3.45(m,1H), 3.6-3.7 (m,1H),                                      4.3-4.4(m,1H), 7.1(m,1H), 7.3- 7.5(m,2H) ppm.      27                                                                               1 #STR373##                                                                             8 #STR374##                                                                            391 (m).sup.+                                                                      .sup.1 H-NMR(CDCl.sub.3): δ = 1.75-1.95(m                               ,2H), 2.05-2.35(m,7H), 2.45-2.55(m,1H), 3.2-                                  3.4(m,3H), 3.65(d,1H), 4.45(d,1H), 5.05                                       (d,1H), 6.8-7.3(m,7H) ppm.                         28                                                                               4 #STR375##                                                                             8 #STR376##                                                                            391 (m).sup.+                                                                      .sup.1 H-NMR(CDCl.sub.3): δ = 1.75-2.2(m,                               6H), 2.35-2.5(m,4H), 3.2-3.35(m,3H), 3.65                                     (d,1H), 4.3(d,1H), 4.7(d,1H), 6.8-6.9 (m,1H),                                 7.05-7.1(m,1H), 7.15-7.3(m,5H) ppm.                29                                                                               2 #STR377##                                                                             8 #STR378##                                                                            454 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 1.8-2.25(m,                               5H), 2.4- 2.55(m,1H), 3.2-3.4(m,4H), 3.7-3.8                                  (m,1H), 4.35(d,1H), 4.95(d,1H), 6.85-                                         7.65(m,12H) ppm.                                   30                                                                               7 #STR379##                                                                             8 #STR380##                                                                            420 (m + 1).sup.+                                                                  .sup.1 H-NMR(d.sub.6 -DMSO): δ =                                        1.05-1.25(m,2H), 1.6-2.05(m,9H),                                              2.15-2.3(m,2H), 3.0-3.2 (m,3H), 3.2-3.3(m,3H),                                3.4-3.5(m,1H), 3.65-3.75(m,1H),                                               4.35-4.45(m,1H), 7.3- 7.4(d,1H),                                              7.55-7.65(m,2H) ppm.                               31                                                                               1 #STR381##                                                                             8 #STR382##                                                                            --   .sup.1 H-NMR(CDCl.sub.3): δ = 1.1-1.15(m,                               1H), 1.8- 2.0(m,2H), 2.0-2.3(m,3H), 2.4-2.5                                   (m,1H), 3.2-3.5(m,3H), 3.6-3.8(m,1H),                                         4.4(d,1H), 4.85(d,1H), 6.75-6.85 (m,1H),                                      7.1-7.5(m,7H) ppm.                                 32                                                                               2 #STR383##                                                                             8 #STR384##                                                                            --   Found: C, 62.49; H, 7.22; N, 3.51. C.sub.20                                   H.sub.27 NCl.sub.2 O.sub.2 requires: C, 62.50;                                H, 7.08; N, 3.64%. .sup.1 H-NMR(CDCl.sub.3):                                  δ = 0.95-1.1(m,2H), 1.15-1.30(m,4H),                                    1.55-1.75(m,6H), 1.85- 2.2(m,5H),                                             2.35-2.45(m,1H), 3.1-3.2 (m,1H),                                              3.35-3.50(m,4H), 3.65-3.75(m,1H),                                             7.1-7.15(m,1H), 7.3-7.4(m,2H)                      __________________________________________________________________________                               ppm.                                           

Preparations 33 to 38

The compounds of the following tabulated Preparations of the generalformula: ##STR385## were prepared by a similar method to that used inPreparation 5 using the appropriate ethanol derivative startingmaterials (see Preparations 8, 27 to 30 and 32).

    __________________________________________________________________________    Prep.               LRMS                                                      No.                                                                              R        R.sup.1 m/z  Analysis/.sup.1 H-NMR                                __________________________________________________________________________    33                                                                               3 #STR386##                                                                            5 #STR387##                                                                           470 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 1.95-2.35(m,8                             H), 2.45-2.6(m,1H), 2.8(s,3H), 3.25(d,1H),                                    3.6-3.75(m,2H), 3.9-4.0(m,1H), 4.25 (d,1H),                                   5.1(d,1H), 6.75-7.3(m,7H) ppm.                       34                                                                               4 #STR388##                                                                            5 #STR389##                                                                           470 (m + 1.sup.+                                                                   .sup.1 H-NMR(CDCl.sub.3): δ = 1.95-2.25(m,6                             H), 2.4 (s,3H), 2.45-2.55(m,1H), 2.85(s,3H),                                  3.6-3.95(m,3H), 4.2(d,1H), 4.9(d,1H),                                         6.8-6.85(m,1H), 7.15-7.3(m,6H) ppm.                  35                                                                               6 #STR390##                                                                            5 #STR391##                                                                           --   .sup.1 H-NMR(CDCl.sub.3): δ = 2.05-2.25(m,5                             H), 2.45-2.55(m,1H), 2.85(s,1H), 3.4(d,1H),                                   3.7-3.95(m,3H), 4.3(d,1H), 5.0(d,1H),                                         6.85-7.65(m,12H) ppm.                                36                                                                               7 #STR392##                                                                            5 #STR393##                                                                           --   .sup.1 H-NMR(CDCl.sub.3): δ = 1.15-1.5(m,2H                             ), 1.6- 1.9(m,5H), 2.0-2.35(m,7H), 2.4-2.53                                   (m,1H), 2.85-3.1(m,3H), 3.2-3.5(m,1H),                                        3.4-3.55(m,2H), 3.65-3.75(m,1H), 3.9-                                         4.05(m,2H), 7.1-7.15(d,1H), 7.3-7.36 (s,1H),                                  7.4-7.5(d,1H) ppm.                                   37                                                                               8 #STR394##                                                                            9 #STR395##                                                                           428 (m).sup.+                                                                      --                                                   38                                                                               0 #STR396##                                                                            1 #STR397##                                                                           --   .sup.1 H-NMR(CDCl.sub.3): δ = 0.9-1.05(m,2H                             ), 1.1- 1.3(m,3H), 1.55-1.75(m,6H), 2.05-2.30                                 (m,5H), 2.35-2.50(m,1H), 2.90(s,3H), 3.1-                                     3.2(m,1H), 3.35-3.45(m,2H), 3.60-3.65 (m,1H),                                 3.9-4.0(m,2H), 7.1-7.15(m,1H), 7.35-7.50(m,2H)                                ppm.                                                 __________________________________________________________________________

Preparations 39 to 43

The compounds of the following tabulated Preparations of the generalformula: ##STR398## were prepared by a similar method to that used inPreparation 6 using the appropriate ethanol derivative startingmaterials (see Preparations 23 to 26 and 31).

    __________________________________________________________________________    Prep.             LRMS                                                        No.                                                                              R      R.sup.1 m/z  Analysis/.sup.1 H-NMR                                  __________________________________________________________________________    39                                                                               1 #STR399##                                                                          5 #STR400##                                                                           --   .sup.1 H-NMR(CDCl.sub.3): δ = 2.1-2.3(m,3H),                            2.4- 2.6(m,2H), 2.85(d,1H), 3.4(d,1H), 3.7 (d,1H),                            4.4(d,1H), 4.8(d,1H), 6.7-7.3 (m,8H), 9.35(s,1H)                              ppm.                                                   40                                                                               2 #STR401##                                                                          5 #STR402##                                                                           350 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 0.95-1.05(m,2H)                           , 1.15-1.3(m,4H), 1.6-2.5(m,9H), 2.65- 2.75(m,1H),                            2.95-3.05(m,1H), 3.1-3.2 (m,1H), 3.4-3.5(m,2H),                               3.7-3.8(m,1H), 7.05-7.3(m,3H), 9.45(s,1H) ppm.         41                                                                               1 #STR403##                                                                          6 #STR404##                                                                           342 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 2.1-2.3(m,2H),                            2.4- 2.55(m,2H), 2.8-2.9(m,1H), 3.3-3.4 (m,2H),                               3.7-3.8(m,1H), 4.45-4.6(m,1H), 4.7-4.8(m,1H),                                 6.9-7.4(m,9H), 9.4 (s,1H) ppm.                         42                                                                               1 #STR405##                                                                          3 #STR406##                                                                           342 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 2.15-2.3(m,2H),                            2.45-2.6(m,2H), 2.8-2.9(m,1H), 3.4-3.5 (m,2H),                               3.75-3.85(m,1H), 4.45(d,1H), 4.8(d,1H),                                       6.95-7.35(m,9H), 9.35 (m,1H) ppm.                      43                                                                               1 #STR407##                                                                          8 #STR408##                                                                           376 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 2.1-2.3(m,2H),                            2.4- 2.7(m,3H), 2.8-2.9(m,1H), 3.4(d,1H),                                     3.75(d,1H), 4.4(d,1H), 4.8(d,1H), 6.8- 6.85(m,1H),                            7.2-7.4(m,7H), 9.4(s,1H) ppm.                          __________________________________________________________________________

Preparations 44 to 52

The compounds of the following tabulated Preparations of the generalformula: ##STR409## were prepared by a similar method to that used inPreparation 7 using the appropriate 2(1H)-piperidone derivatives (seePreparations 3, 20, 21 and 22) and alkyl bromides as the startingmaterials.

    __________________________________________________________________________    Prep.               LRMS                                                      No.                                                                              R        R.sup.1 m/z  Analysis/.sup.1 H-NMR                                __________________________________________________________________________    44                                                                               1 #STR410##                                                                            5 #STR411##                                                                           --   Found: C, 69.55; H, 6.81; N, 2.71. C.sub.25                                   H.sub.29 NF.sub.2 O.sub.3 requires C, 69.91; H,                               6.81; N, 3.26%. .sup.1 H-NMR(CDCl.sub.3):                                     δ = 1.4-1.75(m,8H), 1.85-1.95(m,2H),                                    2.05-2.2(m,2H), 2.4- 2.5(m,1H), 2.8-3.05(m,1H),                               3.3-3.5 (m,3H), 3.6-3.75(m,1H), 4.25-4.4 (m,2H),                              4.9-5.0(m,1H), - # 6.6-6.8(m,2H),                                             6.95-7.05(m,1H), 7.25-7.4(m,5H) ppm.                 45                                                                               2 #STR412##                                                                            5 #STR413##                                                                           436 (m + 1).sup.+                                                                  --                                                   46                                                                               1 #STR414##                                                                            6 #STR415##                                                                           428 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 1.4-1.75(m,7H                             ), 1.85-2.25(m,4H), 2.4-2.55(m,1H), 2.85-                                     3.05(m,1H), 3.3-3.8(m,5H), 4.25-4.45 (m,2H),                                  4.85-4.95(m,1H), 6.85-7.4 (m,9H) ppm.                47                                                                               1 #STR416##                                                                            3 #STR417##                                                                           428 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 1.35-1.6(m,6H                             ), 1.8- 2.2(m,6H), 2.4-2.5(m,1H), 2.85-3.05                                   (m,1H), 3.3-3.85(m,4H), 4.2-4.35 (m,2H),                                      4.9-4.95(m,1H), 6.9-7.35(m,9H) ppm.                  48                                                                               9 #STR418##                                                                            8 #STR419##                                                                           476 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 1.35-2.5(m,15                             H), 2.8-3.1(m,1H), 3.2-3.4(m,3H), 3.45-3.6                                    (m,1H), 3.65-3.7(m,2H), 4.2-4.35 (m,2H),                                      5.0-5.15(m,1H), 6.75-6.85 (m,1H), 7.0-7.1(m,5H)                               ppm.                                                 49                                                                               0 #STR420##                                                                            8 #STR421##                                                                           476 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 1.4-1.75(m,6H                             ), 1.8- 1.9(m,2H), 2.05-2.2(m,3H), 2.4(s,3H),                                 2.4-2.5(m,1H), 2.85-3.1(m,1H), 3.3-3.75 (m,5H),                               4.2-4.35(m,2H), 4.9-4.95 (m,1H), 6.8-6.85(m,1H),                              7.0-7.1(m,1H), 7.15-7.3(m,5H) ppm.                   50                                                                               1 #STR422##                                                                            8 #STR423##                                                                           462 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 1.35-1.7(m,6H                             ), 1.8- 2.05(m,2H), 2.05-2.2(m,2H), 2.35-2.5                                  (m,1H), 2.8-3.1(m,1H), 3.3-3.8(m,6H),                                         4.25-4.4(m,2H), 4.9-5.05(m,1H), 6.7-6.8 (m,1H),                               7.1-7.15(m,1H), 7.2-7.5(m,6H) ppm.                   51                                                                               2 #STR424##                                                                            3 #STR425##                                                                           434 (m).sup.+                                                                      .sup.1 H-NMR(CDCl.sub.3): δ = 0.9-1.1(m,2H)                             , 1.1- 1.3(m,4H), 1.4-1.8(m,11H), 1.85-2.2                                    (m,5H), 2.3-2.5(m,1H), 3.0-3.2(m,2H),                                         3.4-3.6(m,4H), 3.6-3.8(m,2H), 4.3-4.4 (m,1H),                                 7.1-7.4(m,4H) ppm.                                   52                                                                               2 #STR426##                                                                            8 #STR427##                                                                           468 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 0.95-2.2(m,22                             H), 2.35-2.5(m,1H), 3.05-3.25(m,2H), 3.35-                                    3.85(m,6H), 4.35-4.45(m,1H), 7.1-7.15 (m,1H),                                 7.35-7.45(m,2H) ppm.                                 __________________________________________________________________________     .sup.1 Potassium iodide was added to the reaction mixture and then the        mixture heated at 50° C. for four hours.                          

Preparation 53 1-Diphenylmethylazetidin-3-ol

A solution of benzhydrylamine (200 ml, 1.16 mol) and epichlorohydrin(186 ml, 1 mol. equiv.) in methanol (600 ml) was stirred at roomtemperature for five days and then heated at 40° C. for two days. Thesolvent was then removed under reduced pressure, the residue dissolvedin isopropyl alcohol (500 ml) and the solution heated under reflux forsix hours. The solution was cooled to room temperature and theprecipitate filtered off. This solid was partitioned betweendichloromethane (400 ml) and saturated aqueous sodium bicarbonatesolution (500 ml). The aqueous phase was extracted with dichloromethane(2×400 ml) and the combined organic phases dried over magnesiumsulphate. The solution was then filtered and the solvent removed fromthe filtrate under reduced pressure to give the title compound (86 g) asa crystalline solid.

¹ H-NMR (CDCl₃):δ=1.8-2.3 (s,br,1H), 2.85-2.9 (m,2H), 3.5-3.55 (m,2H),4.35 (s,1H), 4.4-4.5 (m,1H), 7.15-7.4 (m,10H) ppm.

Preparation 54 1-Diphenylmethyl-3-methanesulphonyloxyazetidine

To a solution of 1-diphenylmethylazetidin-3-ol (see Preparation 53 (65.9g, 275.7 mmol) in dry dichloromethane (700 ml) at 0° C. under nitrogenwas added triethylamine (57 ml, 1.5 mol. equiv.). After five minutes,methanesulphonyl chloride (25.6 ml, 1.2 mol. equiv.) was added and themixture stirred for one hour. Water (300 ml) was then added and themixture extracted with dichloromethane (3×300 ml). The combined organiclayers were dried over magnesium sulphate. The solution was thenfiltered and the solvent removed from the filtrate under reducedpressure. The residue was chromatographed using silica gel eluting withmethanol:dichloromethane (1.49, by volume) to give the title compound(73.4 g) as a solid.

¹ H-NMR (CDCl₃):δ=2.95 (s,3H), 3.15-3.25 (m,2H), 3.6-3.65 (m,2H), 4.4(s,1H), 5.05-5.15 (m,1H), 7.15-7.4 (m,10H) ppm.

Preparation 55 1-Diphenylmethyl-3-morpholinoazetidine

A solution of 1-diphenylmethyl-3-methanesulphonyloxyazetidine (seePreparation 54) (24.46 g, 7.72 mmol), potassium carbonate (32 g, 3 mol.equiv.) and morpholine (7.34 ml, 1.09 mol. equiv.) in acetonitrile (200ml) was heated under reflux for four hours. The solution was then cooledto room temperature, water (50 ml) added and the mixture concentratedunder reduced pressure. The residue was partitioned between ethylacetate (400 ml) and water (400 ml) and the organic phase separated andwashed with water (2×400 ml). The organic phase was dried over magnesiumsulphate, filtered and the solvent removed from the filtrate underreduced pressure. The residue was then chromatographed using silica geleluting with hexane:diethyl ether (1:1, by volume) to give the titlecompound (16.5 g).

¹ H-NMR (CDCl₃):δ=2.25-2.3 (m,4H), 2.85-3.05 (m,3H), 3.35-3.4 (m,2H),3.7-3.75 (m,4H), 4.45 (s,1H), 7.15-7.45 (m,10H) ppm.

Preparation 56 3-Morpholinoazetidine dihydrochloride

A mixture of 1-diphenylmethyl-3-morpholinoazetidine (see Preparation 55)(18.6 g, 60.4 mmol), palladium hydroxide (2 g), ethanol (200 ml) and 1 Naqueous hydrochloric acid solution (52 ml) was stirred under anatmosphere of hydrogen at 345 kPa (50 p.s.i.) for three days. Thecatalyst was then removed by filtration and the filtrate evaporated todryness. Addition of dichloromethane (100 ml) to the residue andtrituration yielded a solid which was recrystallised from methanol togive the title compound (10.2 g) as a crystalline solid. LRMSm/z=179(m+1)⁺. (N.B. The monohydrochloride, used instead of thedihydrochloride in some reactions, can be similarly prepared using onemolar equivalent of hydrogen chloride.

Preparation 57 3-Cyano-1-(diphenylmethyl)azetidine

To a solution of the compound of Preparation 54 (10 g, 31.5 mmol) indimethylformamide (100 ml) was added a solution of sodium cyanide (4.63g, 3 mol. equiv.) in water (50 ml) in five portions over two minutes.The mixture was then heated at 70° C. for sixteen hours. The reactionwas cooled to room temperature and then poured into an ice-water mixture(300 ml). The brown solid that formed was removed by filtration,dissolved in dichloromethane and the solution dried over anhydrousmagnesium sulphate. The solution was filtered and the solvent removedfrom the filtrate under reduced pressure. The residue was thenchromatographed using silica gel eluting with ethyl acetate:hexane (1:3,by volume) to give the title compound (5.9 g).

¹ H-NMR (CDCl₃):δ=3.2-3.35 (m,3H), 3.45-3.5 (m,2H), 4.4 (s,1H),7.15-7.45 (m,10H) ppm.

Preparation 58 1-(Diphenylmethyl)azetidine-3-carboxyl ic acid

To a suspension of the compound of Preparation 57 (5.9 g, 23.8 mmol) inn-butanol (60 ml) was added a solution of potassium hydroxide (4.8 g) inwater (9 ml), dropwise over three minutes. The mixture was then heatedat 90-100° C. for twenty hours. The reaction was cooled to roomtemperature and the solvent removed under reduced pressure. The residuewas poured into ethyl acetate (100 ml) and water (100 ml). The aqueouslayer was separated and filtered, then acidified to pH4 using 2N aqueoushydrochloric acid solution. The precipitated white solid was filteredoff, washed with ethyl acetate (15 ml) and dried under reduced pressureto give the title compound (3.5 g). LRMS m/z=268(m+1)⁺.

¹ H-NMR (d₆ DMSO):δ=3.1-3.3 (m,5H), 4.4 (br.s,1H), 7.15-7.4 (m,10H),12.3 (br.s,1H) ppm.

Preparation 591-Diphenylmethyl-3-(N-[2-hydroxyethyl]-N-methylcarbamoyl)azetidine

A mixture of 1-diphenylmethylazetidine-3-carboxylic acid (seePreparation 58) (1.8 g, 6.73 mmol), 2-methylaminoethanol (0.76 g, 1.5mol. equiv.), 1-[3-dimethylaminopropyl]-3-ethylcarbodiimidehydrochloride (1.27 g, 1.1 mol. equiv.), 1-hydroxybenzotriazole hydrate(1.08 g, 1.05 mol. equiv.) and N-methylmorpholine (1.5 g, 2.2 mol.equiv.) in dry dichloromethane (50 ml) was stirred at room temperaturefor sixteen hours. The solvent was removed under reduced pressure andthe residue partitioned between ethyl acetate (50 ml) and saturatedaqueous sodium bicarbonate solution (50 ml). The layers were separatedand the aqueous layer further extracted with ethyl acetate (30 ml). Thecombined organic layers were dried over anhydrous sodium sulphate. Thesolution was filtered, the solvent removed from the filtrate underreduced pressure and the residue chromatographed using silica geleluting with methanol:dichloromethane (7:93, by volume) to give thetitle compound (1.76 g). TLC Rf 0.3 (silica, methanol:dichloromethane,7:93, by volume). LRMS m/z=325(m+1)⁺. Found C, 71.99; H, 7.60; N, 8.47.C₂₀ H₂₄ N₂ O₂.0.13 CH₂ Cl₂ requires C, 72.14; H, 7.30; N, 8.36%.

¹ H-NMR (CDCl₃):δ=2.85-2.95 (m,5H), 3.2-3.35 (m,2H), 3.45-3.55 (m,4H),3.65-3.8 (m,2H), 4.4 (s,1H), 7.15-7.45 (m,10H) ppm.

Preparation 601-Diphenylmethyl-3-(N-[2-methoxyethyl)-N-methylcarbamoyl)azetidine

To a solution of the compound of Preparation 59 (0.93 g, 2.87 mmol) intetrahydrofuran (12 ml) at 0° C. under nitrogen was added, in twoportions, 60% w/w sodium hydride dispersion in oil (0.126 g, 1.1 mol.equiv.). After thirty minutes stirring, methyl iodide (0.197 ml, 1.1mol. equiv.) was added and the mixture stirred for sixteen hours. Thesolvent was removed under reduced pressure and the residue partitionedbetween ethyl acetate (50 ml) and saturated aqueous sodium bicarbonatesolution (50 ml). The organic layer was dried over anhydrous sodiumsulphate, filtered and the solvent removed under reduced pressure togive an oil. This crude product was purified by column chromatographyusing silica gel eluting with methanol:dichloromethane (1:19, by volume)to give the title compound (0.95 g). TLC Rf=0.45 (silica, methanol:dichloromethane, 1:19, by volume). LRMS m/z=339 (m+1)⁺. Found: C, 72.42;H, 7.60; N, 7.89. C₂₁ H₂₆ N₂ O₂.0.13 CH₂ Cl₂ requires C, 72.69; H, 7.58;N, 8.03%.

¹ H-NMR (CDCl₃):δ=2.9-2.95 (m,3H), 3.2-3.35 (m,6H), 3.4-3.55 (m,6H), 4.4(m,1H), 7.1-7.45 (m,10H) ppm.

Preparation 61 N-(2-Methoxyethyl)-N-methylcarbamoylazetidinedihydrochloride

To a solution of the compound of Preparation 60 (473 mg, 1.4 mmol) indichloromethane (5 ml) at 0° C. under nitrogen was addedalpha-chloroethyl chloroformate (0.22 ml, 1.1 mol. equiv.), dropwise.After twenty minutes, a further portion of alpha-chloroethylchloroformate (0.1 ml, 0.5 mol. equiv.) was added and the reactionallowed to warm to room temperature over twenty minutes. After thistime, the solvent was removed under reduced pressure, the residuedissolved in methanol (7.5 ml) and potassium carbonate (620 mg, 3 mol.equiv.) was added. The mixture was then heated under reflux for onehour. The reaction mixture was cooled to room temperature, filtered andthe filtrate acidified to pH 3 using ethereal HCl. The solid was removedby filtration. The solvent was removed from the filtrate under reducedpressure to give a gum which was washed several times with diethyl etherand dried under reduced pressure to give the title compound as a crudeproduct (0.35 g) that was used directly.

Preparations 62 to 64

The compounds of the following tabulated Preparations of the generalformula: ##STR428## were prepared by a similar procedure to that ofPreparation 59 using 1-diphenylmethylazetidine-3-carboxylic acid and theappropriate amine as starting materials.

    __________________________________________________________________________    Prep.          LRMS                                                           No.                                                                              --X.sup.1 --R.sup.2                                                                       m/z  Analysis/.sup.1 H-NMR                                     __________________________________________________________________________    62                                                                               1 #STR429## 349 (m + 1).sup.+                                                                  Found: C, 78.75; H, 8.49; N, 8.1. C.sub.23 H.sub.28                           N.sub.2 O requires C, 79.26; H, 8.10; N, 8.04%.                               .sup.1 H-NMR(CDCl.sub.3): δ = 1.1-1.3(m,3H),                            1.35-1.45(m,2H), 1.55-1.75(m,3H), 1.85-1.95(m,2H),                            2.95-3.05(m,1H), 3.25-3.4(m,4H), 3.75-3.85(m,1H),                             4.45(s,1H), 5.95-6.05 (m,1H), 7.15-7.4(m,10H) ppm.        63                                                                               2 #STR430## 321 (m + 1).sup.+                                                                  Found: C, 76.67; H, 6.98; N, 8.02. C.sub.21 H.sub.24                          N.sub.2 O.0.33 CH.sub.2 Cl.sub.2 requires C, 76.64;                           H, 7.38; N, 8.46%. .sup.1 H-NMR(CDCl.sub.3): δ                          = 1.75-1.95(m,4H), 3.2-3.35(m,4H), 3.4-3.5(m,5H),                             4.4(s,1H), 7.15-7.45(m,10H) ppm.                          64                                                                               3 #STR431## 335 (m + 1).sup.+                                                                  Found: C, 78.43; H, 7.93; N, 8.42. C.sub.22 H.sub.26                          N.sub.2 O requires C, 79.00; H, 7.84; N, 8.38%.                               .sup.1 H-NMR(CDCl.sub.3): δ = 1.4-1.7(m,6H),                            3.15-3.35(m,4H), 3.4- 3.55(m,5H), 4.4(s,1H),                                  7.15-7.45(m,10H) ppm.                                     __________________________________________________________________________

Preparations 65 to 68

The hydrochloride salts of the compounds of the following tabulatedPreparations of the general formula: ##STR432## were prepared using asimilar method to that of Preparation 61 using the appropriate azetidinestarting materials (see Preparations 62 to 64 and 105).

    ______________________________________                                        Prep.                 LRMS                                                    No.  --X.sup.1 --R.sup.2                                                                            m/z      Analysis/.sup.1 H-NMR                          ______________________________________                                        65.sup.1                                                                           1 #STR433##      --       --                                             66.sup.1                                                                           2 #STR434##      --       --                                             67.sup.1                                                                           3 #STR435##      --       --                                             68.sup.1,2                                                                         4 #STR436##      --       --                                             ______________________________________                                         Footnotes:                                                                    .sup.1 Crude product used directly in next step.                              .sup.2 Only 1.05 mole equivalents of alphachloroethyl chloroformate were      used and potassium carbonate was not added in the workup procedure.      

Preparation 69 1-(t-Butoxycarbonyl)-3-(3-hydroxypiperidyl)azetidine

A mixture of 1-(t-butoxycarbonyl)-3-methanesulphonyloxyazetidine (seeInternational Patent Application Publication no. WO93/19059) (1.5 g,4.78 mmol) and 3-hydroxypiperidine (1.9 g, 4 mol. equiv.) was heated at110° C. for sixteen hours. The mixture was cooled to room temperatureand partitioned between ethyl acetate (100 ml) and 5% aqueous sodiumbicarbonate solution (100 ml). The layers were separated and the aqueousphase was extracted with a further portion of ethyl acetate (100 ml).The combined organic layers were dried over anhydrous magnesiumsulphate. The solution was filtered, the solvent removed from thefiltrate under reduced pressure and the crude product purified by columnchromatography using silica gel eluting with methanol:dichloromethane(1:9, by volume) to give the title compound (1.4 g). TLC Rf=0.3 (silica,methanol:dichloromethane, 1:9, by volume).

¹ H-NMR (CDCl₃):δ=1.45 (s,9H), 1.5-1.85 (m,6H), 2.15-2.45 (m,4H),3.05-3.15 (m,1H), 3.25-3.95 (m,4H) ppm.

Preparation 70 3-(3-Hydroxypiperidyl)azetidine bistrifluoroacetate

To a solution of the compound of Preparation 69 (1.4 g, 5.8 mmol) indichloromethane (10 ml) at 0° C. under nitrogen was addedtrifluoroacetic acid (5 ml), dropwise. The mixture was then allowed towarm to room temperature and stirred for one hour. The mixture wasconcentrated under reduced pressure, the resulting gum washed withdiethyl ether, then triturated with diethyl ether and filtered to givethe title compound as a white solid (1.2 g). Found: C, 37.32; H, 4.73;N, 7.03. C₈ H₁₆ N₂ O. 2 CF₃ CO₂ H requires C, 37.51; H, 4.72; N, 7.29%.

Preparations 71 to 76

The compounds of the following tabulated Preparations of the generalformula: ##STR437## were prepared using a similar method to that ofPreparation 69 using 1-(t-butoxycarbonyl)-3-methanesulphonyloxyazetidineand the appropriate amines as the starting materials.

    __________________________________________________________________________    Prep.                  LRMS                                                   No.                                                                              --X.sup.1 --R.sup.2 m/z Analysis/.sup.1 H-NMR                              __________________________________________________________________________    71                                                                               5 #STR438##         --  .sup.1 H-NMR(CDCl.sub.3): δ = 1.35-1.5(m,                               10H), 1.55-1.65(m,2H), 1.9-2.1(m,4H),                                         2.6-2.7(m,2H), 3.0-3.1(m,1H), 3.7-3.95 (m,5H)                                 ppm.                                               72                                                                               6 #STR439##         --  .sup.1 H-NMR(CDCl.sub.3): δ = 1.4-1.45(m,                               9H), 1.75-1.85(m,2H), 2.15-2.35(m,2H),                                        2.5-2.7(m,2H), 2.8-2.9(m,1H), 3.2-3.3 (m,1H),                                 3.8-3.95(m,4H), 4.4(br.s,1H) ppm.                  73.sup.1                                                                         7 #STR440##         --  --                                                 74                                                                               8 #STR441##         --  .sup.1 H-NMR(CDCl.sub.3): δ = 1.4(s,9H),                                2.1(s,3H), 2.5(m,3H), 3.25(m,1H), 3.6(t,2H),                                  3.7-3.8(m,2H), 3.95(t,2H), ppm.                    75 --NHCH.sub.2 CH.sub.2 OH                                                                          --  .sup.1 H-NMR(CDCl.sub.3): δ = 1.4(s,9H),                                1.8(m,1H), 2.75(t,2H),                                                        3.45(s,1H), 3.6-3.8(m,5H), 4.0-4.2(m,2H) ppm.      76                                                                               9 #STR442##         --  .sup.1 H-NMR(CDCl.sub.3): δ = 1.45(s,9H),                                2.0-2.25 (m,6H), 2.8-3.15(m,4H),                                             3.8-3.95(m,4H), 7.3- 7.35(m,2H),                                              7.45-7.5(m,1H), 7.65-7.7(m,1H)                     __________________________________________________________________________                               ppm.                                                Footnote:                                                                     .sup.1 In the workup, the reaction mixture was cooled and excess              piperazine removed under reduced pressure. The crude product was used         directly.                                                                

Preparations 77 to 89

The compounds of the following tabulated Preparations of the generalformula: ##STR443## were prepared using a similar method to that used inPreparation 70 using the appropriate azetidine derivative startingmaterials (see Preparations 71,72,74,76, 90, 170 and 172 to 178).

    __________________________________________________________________________    Prep.                  LRMS                                                   No.                                                                              --X.sup.1 --R.sup.2 m/z  Analysis/.sup.1 H-NMR                             __________________________________________________________________________    77.sup.2                                                                         0 #STR444##         --   Found: C, 36.88; H, 4.67; N, 6.93. C.sub.8                                    H.sub.16 N.sub.2 O. 2 CF.sub.3 CO.sub.2 H                                     requires C, 37.51; H, 4.72; N, 7.29%.             78.sup.2                                                                         1 #STR445##         --   Found: C, 35.13; H, 4.14; N, 7.25. C.sub.7                                    H.sub.14 N.sub.2 O. 2 CF.sub.3 CO.sub.2 H                                     requires C, 35.68; H, 4.36; N, 7.57%.             79.sup.2                                                                         2 #STR446##         157 (m + 1).sup.+                                                                  .sup.1 H-NMR(d.sub.6 -DMSO): δ =                                        2.5-2.7(s,3H), 2.8-3.05(m,2H), 3.5-3.6(m,3H),                                 4.0-4.3(m,6H), 8.6-9.0(s,br,2H) ppm.              80.sup.1                                                                         3 #STR447##         157 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 3.3-3.6(m,                                2H), 3.8-4.0(m,2H), 4.0- 4.2(m,4H),                                           4.2-4.4(m,2H), 4.8-5.0(m,1H), 8.6-9.0                                         (s,br,2H) ppm.                                    81.sup.2                                                                         4 #STR448##         --   Found: C, 39.08; H, 5.17; N, 6.78, C.sub.9                                    H.sub.18 N.sub.2 O.2 CF.sub.3 CO.sub.2 H                                      requires: C, 39.20; H, 5.06; N, 7.03%.            82.sup.2                                                                         5 #STR449##         --   Found: C, 40.48; H, 5.37; N, 6.50. C.sub.10                                   H.sub.20 N.sub.2 O.2CF.sub.3 CO.sub.2 H                                       requires: C, 40.78; H, 5.38; N, 6.80%.            83.sup.2                                                                         6 #STR450##         199 (m + 1).sup.+                                                                  --                                                84.sup.2,3                                                                       7 #STR451##         249 (m + 1).sup.+                                                                  .sup.1 H-NMR(d.sub.6 -DMSO): δ =                                        2.4-2.5(m,10H), 3.15- 3.2(m,4H),                                              3.35-3.45(m,1H), 3.8-4.05(m,4H),                                              8.75(s,br.,1H) ppm.                               85.sup.2,3                                                                       8 #STR452##         291 (m + 1).sup.+                                                                  .sup.1 H-NMR(d.sub.6 -DMSO): δ =                                        2.4-2.5(m,4H), 3.1- 3.25(m,7H),                                               3.35-3.4(m,1H), 3.6-3.65(m,3H),                                               3.8-4.05(m,4H), 8.7(s,br.,1H) ppm.                86.sup.2                                                                         9 #STR453##         --   Found: C, 47.04; H, 4.31; N, 8.24. C.sub.15                                   H.sub.19 N.sub.3 O.2CF.sub.3 CO.sub.2 H                                       requires: C, 47.01; H, 4.36; N, 8.66%.            87.sup.2                                                                         0 #STR454##         220 (m + 1).sup.+                                                                  .sup.1 H-NMR(d.sub.6 -DMSO): δ =                                        2.4-2.5(m,2H), 2.9 (s,3H), 3.1-3.2(m,4H),                                     3.3-3.5(m,1H), 3.8-4.0 (m,4H), 8.7-8.9(m,3H)                                  ppm.                                              88.sup.2                                                                         1 #STR455##         199 (m + 1).sup.+                                                                  --                                                89.sup.2,3                                                                       2 #STR456##         235 (m + 1).sup.+                                                                  .sup.1 H-NMR(d.sub.4 -CH.sub.3 OH): δ =                                 1.05-1.1(m,4H), 1.15(s,3H), 1.75-1.8(m,5H),                                   1.95-2.1(m,1H), 2.55-2.7(m,4H),                   __________________________________________________________________________                                ppm.                                               Footnotes:-                                                                   .sup.1 Prepared as the trifluoroacetate salt.                                 .sup.2 Prepared as the bistrifluoroacetate salt.                              .sup.3 A final ethyl acetate trituration was used in the workup.         

Preparation 90 1-(t-Butoxycarbonyl)-3-(2-oxomorpholino)azetidine

To a stirred suspension of sodium hydride (60% w/w dispersion in mineraloil, 0.29 g, 1 mol. equiv.) in toluene (20 ml) at room temperature undernitrogen was added the compound of Preparation 75 (1.57 g, 1 mol.equiv.), portionwise. The reaction was stirred for thirty minutes andthen cooled to 0° C. Ethyl chloroacetate (0.78 ml, 1 mol. equiv.) wasthen added over fifteen minutes, the reaction stirred for a further 1hour at room temperature and then heated under reflux for ninetyminutes. The solution was cooled, diluted with diethyl ether (20 ml) andwashed with saturated aqueous sodium bicarbonate solution (30 ml). Theorganic layer was dried over anhydrous sodium sulphate. The organicsolvent was removed under reduced pressure and the residue purified byflash column chromatography on silica gel eluting withmethanol:dichloromethane (4:96, by volume) to give the title compound(0.8 g). TLC Rf=0.23 (silica, methanol:dichloromethane, 4:96, byvolume).

¹ H-NMR (CDCl₃):δ=1.4 (s,9H), 3.5-3.6 (m,2H), 3.9-4.0 (m,4H), 4.1-4.2(m,4H), 5.2-5.4 (m,1H) ppm.

Preparation 91 1-Diphenylmethyl-3-(2,6-dimethylpiperidinyl)azetidine

1-Diphenylmethyl-3-methanesulphonyloxyazetidine (see Preparation 54) (2g, 1 mol. equiv.) and 2,6-dimethylpiperidine (6.79 ml, 3 mol. equiv.)were heated together at 110° C. under nitrogen for six hours. Saturatedaqueous sodium bicarbonate solution (60 ml) was added and the mixtureextracted with ethyl acetate (3×40 ml). The combined organic extractswere dried using magnesium sulphate. The organic solvent was removedunder reduced pressure and the residue purified by flash columnchromatography on silica gel eluting with methanol:dichloromethane (1:9,by volume) to give the title compound (0.48 g). TLC Rf=0.39 (silica,methanol:dichloromethane, 1:9, by volume). LRMS m/z=335 (m+1)⁺. Found:C, 80.29; H, 9.00; N, 8.14. C₂₃ H₃₀ N₂ 0.125 CH₂ Cl₂ requires C, 80.48;H, 8.84; N, 8.12%.

¹ H-NMR (CDCl₃):δ=1.0 (s,6H), 1.4-1.8 (m,6H), 2.7-2.9 (m,4H), 3.35-3.4(m,2H), 3.7 (s,1H), 4.4 (s,1H), 7.1-7.4 (m,10H) ppm.

Preparations 92 and 93

The compounds of the following tabulated Preparations of the generalformula: ##STR457## (where Ph=phenyl) were prepared by a similar methodto that used in Preparation 91 using1-diphenylmethyl-3-methanesulphonyloxyazetidine and the appropriateamines as the starting materials.

    __________________________________________________________________________    Prep.       LRMS                                                              No.                                                                              --X.sup.1 --R.sup.2                                                                    m/z Analysis/.sup.1 H-NMR                                         __________________________________________________________________________    92                                                                               1 #STR458##                                                                            --  .sup.1 H-NMR(CDCl.sub.3): δ = 1.1(s,6H), 2.2(s,2H),                     2.25(s,3H), 2.8 (t,2H), 3.0(s,1H), 3.15-3.25(m,1H),                           3.35-3.4(m,2H), 4.35 (s,1H), 7.1-7.3(m,6H),                                   7.35-7.4(m,4H) ppm.                                           93                                                                               2 #STR459##                                                                            --  .sup.1 H-NMR(CDCl.sub.3): δ = 2.1(s,3H),                                2.3-2.5(m,2H), 2.55-2.65 (m,1H), 2.8-2.9(m,2H),                               3.1-3.2(m,1H), 3.4-3.45(m,2H), 3.5-3.65(m,2H), 4.4(s,1H),                     7.2-7.4(m,6H), 7.4-7.55 (m,4H) ppm.                           __________________________________________________________________________

Preparation 94 1-Diphenylmethyl-3-(piperidin-1-yl)azetidine

A mixture of 1-diphenylmethyl-3-methanesulphonyloxyazetidine (seePreparation 54) (1.5 g, 1 mol. equiv.), piperidine (0.6 g, 1.5 mol.equiv.) and potassium carbonate (1.31 g, 2 mol. equiv.) in acetonitrile(20 ml) was heated under reflux under nitrogen for four hours. Saturatedaqueous sodium bicarbonate solution and brine were added and the mixtureextracted with ethyl acetate (2×40 ml). The organic extracts werecombined and dried using magnesium sulphate. The organic solvent wasremoved under reduced pressure and the residue purified by flash columnchromatography on silica gel eluting with methanol:dichloromethane (1:9,by volume) to give the title compound (0.65 g). TLC Rf=0.5 (silica,methanol:dichloromethane, 1:9, by volume). LRMS m/z=307(m+1)⁺. Found: C,81.50; H, 8.51; N, 9,02. C₂₁ H₂₆ N₂.0.06 CH₂ Cl₂ requires C, 81.14; H,8.45; N, 8.99%.

¹ H-NMR (CDCl₃):δ=1.4-1.5 (m,2H), 1.5-1.6 (m,5H), 2.1-2.3 (m,4H),2.9-3.0 (m,2H), 3.4-3.5 (m,2H), 4.4 (s,1H), 7.1-7.3 (m,6H), 7.35-7.5(m,4H) ppm.

Preparations 95 to 106

The compounds of the following tabulated Preparations of the generalformula: ##STR460## (where Ph=phenyl) were prepared by a similar methodto that used in Preparation 94 using1-diphenylmethyl-3-methanesulphonyloxyazetidine and the appropriateamines as the starting materials.

    __________________________________________________________________________    Prep.            LRMS                                                         No.                                                                              --X.sup.1 --R.sup.2                                                                         m/z  Analysis/.sup.1 H-NMR                                   __________________________________________________________________________    95                                                                               3 #STR461##   385 (m + 1).sup.+                                                                  Found: C, 80.24; H, 7.28; N, 7.12. C.sub.26                                   H.sub.28 N.sub.2 O.0.06 CH.sub.2 Cl.sub.2 requires                            C, 80.29; H, 7.27; N, 7.19%. .sup.1 H-NMR(CDCl.sub.3                          ): δ = 1.9(t,1H), 2.1-2.25(m,1H), 2.6(d,1H),                            2.8(d,1H), 2.9-3.1(m,3H), 3.3-3.5(m,2H),                                      3.8-3.9(m,1H), 4.0-4.1(m,1H), 4.4(s,1H),                                      4.5-4.6(m,1H), - #7.1-7.5 (m,15H) ppm.                  96                                                                               4 #STR462##   322 (m + 1).sup.+                                                                  Found: C, 75.56; H, 8.48; N, 12.52. C.sub.21                                  H.sub.27 N.sub.3 0.188 CH.sub.2 Cl.sub.2 requires                             C, 75.42; H, 8.18; N, 12.45%. .sup.1 H-NMR(CDCl.sub.                          3): δ = 2.15(s,3H), 2.3-2.6(m,8H), 2.85-3.1                             (m,3H), 3.35-3.45(m,2H), 4.4(s,1H), 7.1-7.3(m,6H),                            7.35-7.55(m,4H) ppm.                                    97                                                                               5 #STR463##   408 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 1.4-1.6(s,9H),                            2.2-2.4(m,4H), 2.8-3.1 (m,3H), 3.3-3.5(m,6H),                                 4.4(m,1H), 7.1-7.5(m,10H) ppm.                          98                                                                               6 #STR464##   391 (m + 1).sup.+                                                                  Found: C, 76.91; H, 7.72; N, 6.88. C.sub.25                                   H.sub.30 N.sub.2 O.sub.2 requires C, 76.89; H,                                7.74; N, 7.18%. .sup.1 H-NMR(CDCl.sub.3): δ =                           1.55(s,1H), 1.6-1.7(m,2H), 1.9-1.95 (m,4H),                                   2.0(s,3H), 2.05-2.1(m,1H), 2.8-2.9(m,2H), 3.0-                                3.05(m,2H), 3.2-3.25(m,1H), 3.35-3.45(m,2H), 4.45                             (s,1H), - #4.95(t,1H), 7.15-7.3(m,6H),                                        7.45-7.55(m,4H) ppm.                                    99                                                                               7 #STR465##   357 (m + 1).sup.+                                                                  Found: C, 66.05; H, 6.72; N, 7.25. C.sub.20                                   H.sub.24 N2O.sub.2 S. 0.125 CH.sub.2 Cl.sub.2                                 requires C, 65.84; H, 6.66; N, 7.63%. .sup.1                                  H-NMR(CDCl.sub.3): δ = 2.75-3.0(m,6H),                                  3.0-3.15(m,4H), 3.15-3.4(m,1H), 3.4-3.5(m,2H),                                4.4-4.5(m,1H), 7.2-7.5 (m,10H) ppm.                     100                                                                              8 #STR466##   323 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 1.8-1.95(m,2H),                           2.4-2.5(m,4H), 2.8- 2.9(m,2H), 3.15-3.3(m,1H),                                3.35-3.45(m,2H), 3.65-3.75 (m,2H), 3.8-3.9(m,2H),                             4.4(s,1H), 7.1-7.3(m,6H), 7.3-7.5 (m,4H) ppm.           101                                                                              9 #STR467##   --   .sup.1 H-NMR(CDCl.sub.3): δ = 2.45-2.6(m,4H),                           2.6-2.7(m,4H), 2.85- 2.95(m,2H), 3.0-3.1(m,1H),                               3.4-3.5(m,2H), 4.45(s,1H), 7.2-7.5(m,10H) ppm.          102.sup.2                                                                        0 #STR468##   350 (m + 1).sup.+                                                                  Found: C, 72.81; H, 7.70; N, 11.31. C.sub.22                                  H.sub.27 N.sub.3 O.05 C.sub.4 H.sub.8 O.sub.2                                 requires C, 73.25; H, 7.94; N, 10.68%. .sup.1                                 H-NMR(CDCl.sub.3): δ = 2.1(s,3H),                                       2.2-2.4(m,4H), 2.85-3.0 (m,3H), 3.3-3.5(m,4H),                                3.6-3.7(m,2H), 4.5(s,1H), 7.2-7.4 (m,6H),                                     7.4-7.5(m,4H) ppm.                                      103                                                                              1 #STR469##   357 (m + 1).sup.+                                                                  Found: C, 66.05; H, 6.72; N, 7.25. C.sub.20                                   H.sub.24 N.sub.2 O.sub.2 S.0.125 CH.sub.2 Cl.sub.2                            requires C, 65.84; H, 6.66; N, 7.63%. .sup.1                                  H-NMR(CDCl.sub.3): δ = 2.7-2.9(m,6H),                                   3.0-3.1(m,4H), 3.15- 3.25(m,1H), 3.35-3.5(m,2H),                              4.4-4.5(m,1H), 7.1-7.4 (m,10H) ppm.                     104                                                                              2 #STR470##   379 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 1.2(s,9H),                                1.4-1.6(m,2H), 1.6-1.7(m,2H), 1.9-2.0(m,2H),                                  2.55-2.65(m,2H), 2.8-3.0(m,3H), 3.3-3.45(m,3H),                               4.2(s,1H), 7.1- 7.3(m,6H), 7.35-7.45(m,4H) ppm.         105                                                                              3 #STR471##   379 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 1.2-1.25(m,3H),                           1.65-1.9 (m,6H), 2.2-2.3(m,1H), 2.65-2.7(m,2H),                               2.8-2.95 (m,3H), 3.35-3.4(m,2H), 4.1-4.15(m,2H),                              4.4 (s,1H), 7.15-7.3(m,6H), 7.35-7.4(m,4H) ppm.         106                                                                              4 #STR472##   --   .sup.1 H-NMR(CDCl.sub.3): δ = 1.35-1.45(m,11H)                          , 1.85- 1.95(m,4H), 2.6-2.7(m,2H), 2.85-2.95(m,3H),                           3.35-3.45(m,3H), 4.35-4.4(m,2H), 7.15-7.3 (m,6H),                             7.35-7.4(m,4H) ppm.                                     __________________________________________________________________________     Footnotes                                                                     .sup.1 Homomorpholine hydrochloride (see Preparation 127) was used as the     amine starting material.                                                      .sup.2 The pH of the reaction mixture was adjusted to 9 using                 Nmethylmorpholine prior to heating under reflux.                         

Preparation 107 3-(Piperidin-1-yl)azetidine dihydrochioride

To a solution of the compound of Preparation 94 (0.64 g) in drydichloromethane (7 ml) at 0° C. under nitrogen was added α-chloroethylchloroformate (0.3 ml, 1 mol. equiv.) and the reaction stirred forthirty minutes. The solvent was removed under reduced pressure and theresidue redissolved in methanol (10 ml) and heated under reflux forforty five minutes. The solvent was then removed under reduced pressureand the resultant gum triturated with diethyl ether (5 ml) to give thetitle compound as a beige powder (0.14 g). LRMS m/z=141 (m+1)⁺.

¹ H-NMR (d₆ -DMSO):δ=1.3-1.4 (m,1H), 1.7-1.9 (m,5H), 2.7-2.9 (m,2H),3.3-3.5 (m,2H), 4.1-4.2 (m,3H), 4.4-4.6 (m,2H), 9.15 (s,br,1H), 9.7(s,br, 1H), 12.0 (s,br, 1H) ppm.

Preparations 108 to 119

The compounds of the following tabulated Preparations of the generalformula: ##STR473## were prepared using a similar procedure to that ofPreparation 107 using the appropriate azetidine derivative startingmaterials (see Preparations 91,92,95,96,98 to 103, 104 and 120).

    __________________________________________________________________________    Prep.                LRMS                                                     No.                                                                              --X.sup.1 --R.sup.2                                                                             m/z  Analysis/.sup.1 H-NMR                               __________________________________________________________________________    108.sup.1                                                                        5 #STR474##       219 (m + 1).sup.+                                                                  .sup.1 H-NMR(d.sub.6 -DMSO): δ = 2.7-2.9(m                              ,2H), 3.2-3.6(m,4H), 3.9-4.1(m,5H)                                            4.3-4.5(m,2H), 4.8(d,1H); 7.3-7.4(m,5H),                                      9.15(s,br,1H), 9.6(s,br,1H) ppm.                    109.sup.1                                                                        6 #STR475##       156 (m + 1).sup.+                                                                  .sup.1 H-NMR(d.sub.6 -DMSO): δ = 2.6-2.8(m                              ,3H), 2.9-3.1(m,4H), 3.05-3.1(m,2H),                                          3.3-3.5(m,2H), 3.8-4.0(m,5H), 9.0-9.5 (m,2H),                                 11.0(m,1H) ppm.                                     110.sup.1                                                                        7 #STR476##       169 (m + 1).sup.+                                                                  .sup.1 H-NMR(d.sub.6 -DMSO): δ = 1.2-1.3(m                              ,4H), 1.4-2.0(m,8H), 3.3-3.4(m,1H),                                           3.5-4.2(m,3H), 4.6-4.8(m,3H), 9.2 (s,br,1H),                                  10.0(s,br,1H) ppm.                                  111.sup.1                                                                        8 #STR477##       159 (m + 1).sup.+                                                                  .sup.1 H-NMR(d.sub.6 -DMSO): δ = 1.1(s,3H)                              , 2.8-2.9(m,2H), 2.9-3.1 (m,1H), 3.2-3.6(m,9H),                               4.0-4.4(m,2H), 9.2(s,br,1H), 9.4 (s,br,1H)                                    ppm.                                                112.sup.1                                                                        9 #STR478##       145 (m + 1).sup.+                                                                  --                                                  113.sup.1                                                                        0 #STR479##       --   --                                                  114.sup.2                                                                        1 #STR480##       191 (m + 1).sup.+                                                                  .sup.1 H-NMR(d.sub.6 -DMSO): δ = 2.8-3.0(m                              ,4H), 3.1-3.2(m,4H), 3.6-3.8(m,1H),                                           3.8-4.0(m,4H), 9.1(s,br,1H), 9.3(s,br,1H) ppm.      115.sup.1                                                                        2 #STR481##       157 (m + 1).sup.+                                                                  .sup.1 H-NMR(d.sub.6 -DMSO): δ = 2.4-3.5(m                              ,10H), 3.6-3.8(m,1H), 3.8-4.0(m,4H),                                          9.2(s,br,1H), 9.4-9.9(m,2H) ppm.                    116.sup.1                                                                        3 #STR482##       159 (m + 1).sup.+                                                                  .sup.1 H-NMR(d.sub.6 -DMSO): δ = 2.6-3.8(m                              ,8H), 3.8-4.5(m,5H), 9.1 (s,br,1H),                                           9.7(s,br,1H), ppm.                                  117.sup.1                                                                        4 #STR483##       --   --                                                  118.sup.1                                                                        5 #STR484##       191 (m + 1).sup.+                                                                  .sup.1 H-NMR(d.sub.6 DMSO): δ = 2.8-2.95(m                              ,4H), 3.05-3.2(m,4H), 3.6-3.8(m,1H),                                          3.8-4.0(m,4H), 9.0-9.2(s,br,1H), 9.2-9.4                                      (s,br,1H) ppm.                                      119.sup.1                                                                        6 #STR485##       213 (m + 1).sup.+                                                                  --                                                  __________________________________________________________________________     Footnotes:                                                                    .sup.1 Obtained as the dihydrochloride salt.                                  .sup.2 Obtained as the hydrochloride salt.                               

Preparation 120 1-Diphenylmethyl-3-(N-f2-methoxyethyl]-N-methylamino)azetidine

To a solution of the compound of Preparation 93 (0.85 g, 1 mol. equiv.)in tetrahydrofuran (12 ml) at 0° C. under nitrogen was added 60% w/wsodium hydride dispersion in oil (0.126 g, 1.1 mol. equiv.) and thereaction stirred at room temperature for one hour. Methyl iodide (0.448g, 1.1 mol. equiv.) was then added to the mixture and the reactionstirred for a further two hours. A portion of the solvent (10 ml) wasremoved under reduced pressure saturated aqueous sodium bicarbonatesolution (25 ml) was added and the mixture extracted with ethyl acetate(3×35 ml). The combined organic extracts were dried using magnesiumsulphate. The organic solvent was removed under reduced pressure and theresidue purified by flash column chromatography on silica gel elutingwith methanol:dichloromethane (4:96, by volume) to give the titlecompound (0.64 g). TLC Rf=0.3 (silica, methanol:dichloromethane, 4:96,by volume). LRMS m/z=311 (m+1)⁺.

¹ H-NMR (CDCl₃):δ=2.1 (s,3H), 2.4 (t,2H), 2.85-2.95 (m,2H), 3.0-3.1(m,1H), 3.3 (s,3H), 3.4-3.45 (m,4H), 4.4 (s,1H), 7.15-7.3 (m,6H),7.4-7.45 (m,4H) ppm.

Preparation 121 3-(4-t-Butoxycarbonylpiperazinyl)azetidine hydrochloride

The compound of Preparation 97 (1.471 g, 1 mol. equiv.) was dissolved ina mixture of 1 M aqueous hydrochloric acid solution (4 ml) and ethanol(16.6 ml) and 10% palladium-on-carbon (14.7 mg) was added. The mixturewas stirred under an atmosphere of hydrogen at 345 kPa (50 psi) forsixteen hours. The catalyst was then filtered off and the solventremoved under reduced pressure, removing final traces of water byazeotroping with ethanol, to give the title compound as a cream solid(0.83 g) which was used without further purification. TLC Rf=0.84(silica, ethyl acetate:hexane, 1:2, by volume). LRMS m/z=242(m+1)⁺.Found: C, 50.30; H, 8.33; N, 14.39. C₁₂ H₂₃ N₃ O₂.HCl. 0.5 H₂ O requiresC, 50.25; H, 8.79; N, 14.65%.

¹ H-NMR (d₆ -DMSO):δ=1.4 (s,9H), 2.3-2.5 (m,4H), 3.4-3.5 (m,6H), 3.9-4.2(m,4H), 9.7 (s,br,1H) ppm.

Preparation 122 4-Acetyl-1-(t-butoxycarbonyl)piperazine

To a solution of N-t-butoxycarbonylpiperazine (7 g, 1 mol. equiv.) indichloromethane (140 ml) at 0° C. under nitrogen was added triethylamine(6.29 ml, 1.2 mol. equiv.). The reaction mixture was vigorously stirredand acetyl chloride (3.21 ml, 1.2 mol. equiv.) was added, dropwise. Themixture was stirred for twenty four hours. The reaction mixture waswashed with saturated aqueous sodium bicarbonate solution (30 ml), andthe organic layer dried using magnesium sulphate. The organic solventwas removed under reduced pressure and the residue purified by flashcolumn chromatography on silica gel eluting with methanol:ethyl acetate(1:19, by volume) to give the title compound (8.19 g). TLC Rf=0.33(silica, methanol:ethyl acetate, 1:19, by volume). LRMS m/z=229(m+1)⁺.Found: C, 57.83; H, 8.83; N, 12.27. C₁₁ H₂₀ N₂ O₃ requires C, 57.87; H,8.92; N, 12.14%.

¹ H-NMR (CDCl₃):δ=1.4 (s,9H), 2.1 (s,3H), 3.3-3.4 (m,6H), 3.5-3.6 (m,2H)ppm.

Preparation 123 N-Acetylpiperazine trifluoroacetate

To a solution of the compound of Preparation 122(8.2 g, 1 mol. equiv.)in dichloromethane (78 ml) at 0° C. under nitrogen was addedtrifluoroacetic acid (39 ml). The mixture was then warmed to roomtemperature and stirred for a further thirty minutes. The solvent wasthen evaporated under reduced pressure and the resulting oil azeotropedwith dichloromethane (30 ml) to give the title compound as a gum (11.7g). LRMS m/z=129(m+1)⁺.

¹ H-NMR (CDCl₃):δ=2.0 (s,3H), 3.0-3.2 (m,4H), 3.5-3.7 (m,4H), 8.8-9.0(s,br,2H) ppm.

Preparation 124 Pyran-4-one oxime

To a solution (240 ml) of hydroxylamine hydrochloride (60.53 g, 4 mol.equiv.) in water (240 ml) was carefully added 3.6M aqueous sodiumhydroxide solution (240 ml). Pyran-4-one (20 g, 1 mol. equiv.) was addedover a five minute period. The mixture was heated under reflux for oneand a half hours, cooled and then stirred for a further eighteen hoursat room temperature. The reaction mixture was extracted withdichloromethane (4×50 ml) and the combined extracts dried over magnesiumsulphate. Removal of the solvent under reduced pressure gave the titlecompound as a white solid (18.86 g).

¹ H-NMR (CDCl₃):δ=2.4 (t,2H), 2.7 (t,2H), 3.7-3.9 (m,4H), 7.35 (s,1H)ppm.

Preparation 125 Homomorpholin-5-one

To methanesulphonic acid (228.8 ml, 27 mol. equiv.) under nitrogen wasadded, portionwise, phosphorous pentoxide (37.72 g, 2 mol. equiv.) overfive minutes. The solution was stirred at room temperature for two hoursand then pyran-4-one oxime (see Preparation 124)(14.97 g, 1 mol. equiv.)was added, portionwise, over ten minutes. The mixture was heated slowlyto 100° C. and stirred for one hour at this temperature. The reactionwas then further stirred for eighteen hours at room temperature. Themixture was slowly added to water (500 ml) and sodium bicarbonate wasadded, portionwise, until the mixture was basic (pH 9). The mixture wasfiltered and the pad washed several times with dichloromethane (3×50ml). The filtrate was extracted with dichloromethane (7×60 ml). Thecombined extracts were dried over magnesium sulphate, filtered and thefiltrate evaporated under reduced pressure. The resulting solid wastriturated with diethyl ether to give the title compound as a white foam(2.1 g). LRMS m/z=16(m+1)⁺.

¹ H-NMR (CDCl₃):δ=2.6-2.8 (m,2H), 3.3-3.4 (m,2H), 3.7-3.9 (m,4H), 6.2(s,br.,1H) ppm.

Preparation 126 4-(t-Butoxycarbonyl)homomorpholine

To a stirred suspension of lithium aluminium hydride (777 mg, 2 mol.equiv.) in tetrahydrofuran (87 ml) under nitrogen at the refluxtemperature was slowly added a solution of homomorpholin-5-one (seePreparation 125) (1.1 g, 1 mol. equiv.) in tetrahydrofuran (37 ml) overthirty minutes. The mixture was heated under reflux for two hundred andten minutes, cooled to room temperature and a 1:1 v/vtetrahydrofuran:water solution (25 ml) added slowly over ten minutes,followed by 1M aqueous sodium hydroxide solution (1.24 ml). The mixturewas cooled to 0° C. and a solution of di-tert-butyl dicarbonate (2.46 g,1.1 mol. equiv.) in dichloromethane (25 ml) was added over fifteenminutes. The reaction was then allowed to warm to room temperature andstirred for sixteen hours. Sodium sulphate (25 g) was added to themixture with vigorous stirring. The resulting granular white solid wasfiltered off and washed several times with dry dichloromethane. Thecombined filtrates and washings were then evaporated under reducedpressure and the residue dissolved in dichloromethane (50 ml). Thesolution was dried over magnesium sulphate, filtered and the filtrateevaporated under reduced pressure to give an oil. This oil was purifiedusing flash column chromatography on silica gel eluting with ethylacetate:hexane (1:1, by volume) to give the title compound (1.7 g). TLCRf=0.5 (silica, ethyl acetate:hexane, 1:1, by volume).

¹ H-NMR (CDCl₃):δ=1.5 (s,9H), 1.8-2.0 (m,2H), 3.45-3.6 (m,4H), 3.7-3.8(m,4H) ppm.

Preparation 127 Homomorpholine hydrochloride

The compound of Preparation 126 (1.7 g) was dissolved in ethyl acetate(51 ml) and the solution cooled to 0° C. Dry hydrogen chloride gas wasthen bubbled into the mixture for thirty minutes and the reactionstirred for a further thirty minutes. Nitrogen was then bubbled into thesolution for sixteen hours. During this time a white solid precipitatedwhich was filtered off and then washed with cold ethyl acetate (5 ml).The white solid was then dried under reduced pressure for four hours togive the title compound (0.92 g).

¹ H-NMR (CDCl₃):δ=2.25-2.4 (m,2H), 3.25-3.45 (m,4H), 3.9 (t,2H),3.95-4.0 (m,2H), 9.75 (s,br,2H) ppm.

Preparation 128 4-Benzyloxycarbonylthiomorpholine

To a solution of thiomorpholine (5 g, 1 mol. equiv.) and triethylamine(5.4 g, 1.1 mol. equiv.) in dichloromethane (200 ml) at 0° C. undernitrogen was slowly added benzyl chloroformate (8.68 g, 1.05 mol.equiv.) over fifteen minutes. The reaction was then allowed to warm toroom temperature and stirred for a further sixteen hours. The reactionwas washed with a saturated aqueous sodium bicarbonate solution. Theorganic layer was dried using magnesium sulphate, filtered and thesolvent removed under reduced pressure. The residue was purified byflash column chromatography on silica gel eluting with dichloromethaneto give the title compound (10 g). TLC=Rf 0.3 (silica, dichloromethane).Found: C, 59.24; H, 6.49; N, 5.78. C₁₂ H₁₅ NO₂ S requires C, 59.12; H,6.23: N, 5.70%.

¹ H-NMR (CDCl₃):δ=2.5-2.75 (m,4H), 3.7-3.9 (m,4H), 5.15 (s,2H), 7.2-7.4(m,5H) ppm.

Preparation 129 4-Benzyloxycarbonylthiomorpholine-1,1-dioxide

To a solution of 4-benzyloxycarbonylthiomorpholine (see Preparation 128)(4.11 g, 1 mol. equiv.) in dichloromethane (240 ml) under nitrogen wasadded meta-chloroperbenzoic acid (11.96 g, 2.2 mol. equiv.) and thereaction stirred for sixteen hours at room temperature. The resultantsolid that formed was filtered off and the filtrate washed with asaturated aqueous sodium carbonate solution. The organic layer was driedover magnesium sulphate, filtered, and evaporated to dryness underreduced pressure. The resultant solid was then purified by flash columnchromatography on silica gel eluting with dichloromethane: methanol(95:5, by volume) to give the title compound (0.83 g). TLC Rf=0.75(silica, methanol:dichloromethane, 1:19, by volume). Found:C, 53.21; H,5.68; N, 5.14. C₁₂ H₁₅ NO₄ S requires C, 53.51; H, 5.61: N; 5.20%.

¹ H-NMR (CDCl₃):δ=2.9-3.1 (m,4H), 3.9-4.05 (m,4H), 5.15 (s,2H), 7.35-7.5(m,5H) ppm.

Preparation 130 Thiomorpholine-1,1-dioxide

The compound of Preparation 129 (3.5 g, 1 mol. equiv.) was dissolved ina methanol (120 ml) and 10% palladium on carbon (0.4 g) added. Themixture was then stirred under hydrogen at atmospheric pressure for fourand a half hours. The catalyst was filtered off and the solvent removedunder reduced pressure, final traces of methanol being removed byazeotroping with dichloromethane. This gave the title compound as an oilwhich was used without further purification (1.6 g). TLC=Rf 0.3 (silica,ammonium hydroxide:methanol:dichloromethane, 1:10:90, by volume). LRMSm/z=136(m+1)⁺.

¹ H-NMR (CDCl₃):δ=2.95-3.05 (m,4H), 3.35-3.45 (m,5H) ppm.

Preparation 131 1-(t-Butoxycarbonyl)-4-methanesulphonylpiperazine

To a solution of 1-(t-butoxycarbonyl)piperazine (7 g, 1 mol. equiv.) indichloromethane (ml) at 0° C. under nitrogen was added triethylamine(6.29 ml, 1.2 mol. equiv.). The mixture was vigorously stirred whilstmethanesulphonyl chloride (3.49 ml, 1.2 mol. equiv.) was added,dropwise. The mixture was then stirred for twenty four hours. Thereaction mixture was washed with a saturated aqueous sodium bicarbonatesolution (30 ml) and the organic layer dried using magnesium sulphate.The organic solvent was removed under reduced pressure and the residuepurified by flash column chromatography on silica gel eluting with ethylacetate:hexane (1:2, by volume) to give the title compound (6.93 g). TLCRf=0.37 (silica, ethyl acetate:hexane, 1:2, by volume). LRMSm/z=282(m+NH₄)⁺. Found: C, 45.25; H, 7.68; N, 10.49. C₁₀ H₂₀ N₂ SO₄requires C, 45.43; H, 7.63; N, 10.60%.

¹ H-NMR (CDCl₃):δ=1.4 (s,9H), 2.8 (s,3H), 3.15-3.2 (m,4H), 3.5-3.6(m,4H) ppm.

Preparation 132 1-Methanesulphonylpiperazine trifluoroacetate

To a solution of the compound of Preparation 131(6.9 g, 1 mol. equiv.)in dichloromethane (78 ml) at 0° C. under nitrogen was addedtrifluoroacetic acid (28 ml). The mixture was then warmed to roomtemperature and stirred for a further thirty minutes. The solvent wasremoved under reduced pressure and the resulting oil azeotroped withdichloromethane (30 ml). The resultant gum was triturated with diethylether (10 ml) giving the title compound as a white solid (7 g). LRMSm/z=164(m)⁺. Found: C, 30.10; H, 4.80; N, 10.00. C₅ H₁₂ N₂ SO₂ .CF₃ CO₂H requires C, 30.21; H, 4.71; N, 10.07%.

¹ H-NMR (d₆ -DMSO):δ=2.9 (s,3H), 3.1-3.2 (m,4H), 3.3-3.4 (m,4H), 9.0-9.2(s,br,2H) ppm.

Preparation 1331-Diphenylmethyl-3-(4-methanesulphonylpiperazin-1-yl)azetidine

A solution of the compound of Preparation 54 (1.5 g, 1 mol. equiv.),N,N-diisopropylethylamine (7.4 ml, 9 mol. equiv.) and1-methanesulphonylpiperazine (see Preparation 113) (1.97 g, 1.5 mol.equiv.) in acetonitrile (20 ml) under nitrogen was stirred and heatedunder reflux for eighteen hours. Saturated aqueous sodium bicarbonatesolution (45 ml) was added and the mixture extracted with ethyl acetate(3×60 ml). The organic extracts were combined and dried using magnesiumsulphate. The organic solvent was removed under reduced pressure and theresidue purified by flash column chromatography on silica gel elutinginitially with diethyl ether and then with methanol:ethyl acetate (1:9,by volume) to give the title compound (0.38 g). TLC Rf=0.51 (silica,methanol:ethyl acetate, 1:9, by volume). LRMS m/z=350(m+1)⁺.

¹ H-NMR (CDCl₃):δ=2.3-2.4 (m,4H), 2.7 (s,3H), 2.9-3.0 (m,2H), 3.0-3.2(m,1H), 3.2-3.3 (m,4H), 3.4-3.5 (m,2H), 4.4 (s,1H), 7.2-7.4 (m,6H),7.4-7.5 (m,4H) ppm.

Preparation 134 3-(4-Methanesulphonylpiperazin-1-yl)azetidinedihydrochloride

To a solution of the compound of Preparation 133 (0.350 g, 1 mol.equiv.) in dichloromethane (5 ml) at 0° C. was added α-chloroethylchloroformate (0.15 ml, 1.5 mol. equiv.) and the reaction stirred fortwenty four hours. The solvent was removed under reduced pressure andthe residue dissolved in methanol (10 ml) and heated under reflux forone hour. The mixture was then adjusted to pH 3 using a saturatedsolution of hydrogen chloride in diethyl ether and filtered. Thefiltrate was evaporated to dryness under reduced pressure and theresultant gum triturated with diethyl ether (5 ml) to give the titlecompound as a white solid (0.12 g). LRMS m/z=219 (m)⁺.

Preparation 135 Endo-3-Acetoxy-8-methyl-8-azabicyclo[3,2,1 ]octane

A mixture of tropine (10 g), acetic anhydride (20 ml) and pyridine (1ml) was stirred at room temperature for twenty hours under nitrogen. Themixture was then poured onto ice, four drops of concentratedhydrochloric acid were added and the solution was allowed to stand forthirty minutes. A portion of the solvent was removed under reducedpressure and the mixture was partitioned between saturated aqueoussodium bicarbonate solution (20 ml) and ethyl acetate (50 ml). Thelayers were separated and the aqueous layer further extracted with ethylacetate (2×50 ml). The organic extracts were combined and dried (MgSO₄).The solvent was removed under reduced pressure to give the titlecompound (4 g). TLC Rf=0.2 (silica, ammoniumhydroxide:methanol:dichloromethane, 1:9:90, by volume).

¹ H-NMR (CDCl₃):δ=1.6-1.7 (m,2H), 1.9-2.2 (m,7H), 2.05-2.15 (m,2H), 2.25(s,3H), 3.1-3.2 (m,2H), 5.1 (t,1H) ppm.

Preparation 136 Endo-3-Acetoxy-8-azabicyclo[3,2,1]octane hydrochloride

To a solution of the compound of Preparation 135 (3.8 g, 1 mol. equiv.)in dry 1,2-dichloroethane (40 ml) at 0° C. under nitrogen was addedα-chloroethyl chloroformate (2.37 ml, 1 mol. equiv.) and the reactionstirred for thirty minutes. The solvent was then removed under reducedpressure and the residue dissolved in methanol (50 ml) and heated underreflux for one hour. The solvent was then removed under reduced pressureand the resultant gum triturated with diethyl ether (10 ml) and ethylacetate (5 ml) to give the title compound as a yellow powder (3.7 g).

¹ H-NMR (d₆ -DMSO):δ=1.8-2.4 (m,11H), 3.8-4.0 (m,2H), 4.9-5.0 (m,1H),8.9-9.4 (m,2H) ppm.

Preparation 1375(S)-1-Cyclopropylmethyl-5-(3,4-dichlorophenyl)-5-formylmethyl-2-piperidone

Into a solution of the compound of Preparation 141 (0.763 g, 1 mol.equiv.) in methanol (24 ml) under nitrogen at -78° C. was bubbled ozoneat a rate of 50 ml/min. (using a charge of 1.5A to generate the ozonefrom oxygen) for thirty minutes. After this time the amperage wasreduced to zero and oxygen bubbled through the reaction at a rate of 5ml/min. for two minutes. The oxygen supply was then removed and nitrogenbubbled through the reaction mixture for twenty minutes. After this timea solution of dimethyl sulphide (1.7 ml, 10 mol. equiv.) in methanol(3.5 ml) was cautiously added dropwise and the reaction left to warm toroom temperature over eighteen hours. The solvent was removed underreduced pressure and the reaction mixture was partitioned between ethylacetate (20 ml) and water (15 ml). The organic layer was separated andthe aqueous portion further extracted with ethyl acetate (2×20 ml). Theorganic layers were then combined, dried using sodium sulphate, filteredand the filtrate evaporated to dryness under reduced pressure to givethe title compound (0.69 g) which was used without further purification.TLC R_(f) =0.31 (silica, ethyl acetate). LRMS m/z=340(m)⁺.

¹ H-NMR (CDCl₃):δ=0.2-0.4 (m,2H), 0.5-0.7 (m,2H), 1.0-1.15 (m,1H),2.0-2.25 (m,2H), 2.3-2.45 (m,1H), 2.6-2.8 (m,1H), 2.9-3.05 (m,1H),3.1-3.2 (m,1H), 3.4-3.6 (m,2H), 3.9-4.0 (m,1H), 4.05-4.15 (m,1H),7.15-7.2 (m,1H), 7.3-7.5 (m,2H), 9.5 (s,1H) ppm.

Preparations 138 to 140

The compounds of the following tabulated Preparations of the generalformula: ##STR486## were prepared by a similar method to that used inPreparation 137 using the appropriate allylpiperidone starting materials(see Preparations 142 to 144).

    __________________________________________________________________________    Prep.     LRMS                                                                No.                                                                              R      m/z  Analysis/.sup.1 H-NMR                                          __________________________________________________________________________    138                                                                              1 #STR487##                                                                          --   .sup.1 H-NMR(CDCl.sub.3): δ = 2.1-2.3(m,3H),                            2.4-2.6(m,2H), 2.8- 2.85(m,1H), 3.4(d,1H), 3.7(d,1H),                         4.4(d,1H), 4.8(d,1H), 6.95(d,1H), 7.2-7.4(m,7H), 9.4(s,1H)                    ppm.                                                           139.sup.1                                                                        2 #STR488##                                                                          384.5 (m + 1).sup.+                                                                .sup.1 H-NMR(CDCl.sub.3): δ = 0.9-1.1(m,2H),                            1.1-1.35(m,3H), 1.5- 1.8(m,6H), 2.1-2.3(m,3H),                                2.35-2.5(m,1H), 2.7(d,1H), 2.95(d,1H), 3.1-3.15(m,1H),                        3.3-3.55(m,2H), 3.8(d,1H), 7.15(d,1H), 7.4-7.5(m,2H),                         9.5(s,1H) ppm.                                                 140                                                                              3 #STR489##                                                                          --   .sup.1 H-NMR(CDCl.sub.3): δ = 1.3-1.6(m,4H),                            1.6-1.9(m,4H), 2.0- 2.3(m,4H), 2.3-2.5(m,1H), 2.7(d,1H),                      2.95(d,1H), 3.2- 3.3(m,1H), 3.4-3.6(m,2H), 3.8(d,1H),                         7.2(d,1H), 7.4-7.5 (m,2H), 9.5(s,1H) ppm.                      __________________________________________________________________________     Footnote:                                                                     .sup.1 Purified by flash column chromatography eluting with a solvent         gradient of ethyl acetate:hexane (60:40 to 100:0, by volume).            

Preparation 1415(S)-5-Allyl-1-cyclopropylmethyl-5-(3,4-dichlorophenyl)-2-piperidone

Potassium hydroxide (0.78 g, 1 mol. equiv.) was added portionwise todimethyl sulphoxide under nitrogen and the mixture stirred for fifteenminutes at room temperature. To this solution was added a solution ofthe compound of Preparation 145 (0.982 g, 1 mol. equiv.) andcyclopropylmethyl bromide (0.37 ml, 1.1 mol. equiv.) in dimethylsulphoxide (20 ml). The reaction was stirred at room temperature foreighteen hours.

The reaction mixture was partitioned between ethyl acetate (50 ml) andwater (20 ml) and the aqueous layer removed. The organic layer was thenwashed with water (3×20 ml), dried using sodium sulphate, filtered andevaporated to dryness under reduced pressure. The resulting gum waspurified by flash column chromatography on silica gel eluting withmethanol:dichloromethane (1:19, by volume) to give the title compound(0.763 g). TLC R_(f) =0.33 (silica, methanol:dichloromethane, 1:19, byvolume). LRMS m/z=338 (m)⁺.

¹ H-NMR (CDCl₃):δ=0.2-0.4 (m,2H), 0.5-0.7 (m,2H), 1.0-1.15 (m,1H),2.0-2.25 (m,3H), 2.3-2.6 (m,3H), 3.1-3.25 (m,1H), 3.4-3.6 (m,2H),3.65-3.8 (m,1H), 5.0-5.05 (m,2H), 5.2-5.5 (m,1H), 7.15-7.2 (m,1H),7.4-7.5 (m,2H) ppm.

Preparations 142 to 144

The compounds of the following tabulated Preparations of the generalformula: ##STR490## were prepared by a similar method to that used inPreparation 141 using the same piperidone and the appropriate bromo- orp-toluenesulphonyloxyalkane derivative starting materials.

    __________________________________________________________________________    Prep.     LRMS                                                                No.                                                                              R      m/z  Analysis/.sup.1 H-NMR                                          __________________________________________________________________________    142.sup.1                                                                        1 #STR491##                                                                          --   .sup.1 H-NMR(CDCl.sub.3): δ = 1.95-2.05(m,1H),                          2.1-2.3(m,3H), 2.4-2.55(m,2H), 3.25(d,1H), 3.5(d,1H),                         4.4(d,1H), 4.8-5.0(m,3H), 5.2-5.4(m,1H), 6.8(d,1H),                           7.1-7.4(m,7H) ppm.                                             143.sup.1                                                                        2 #STR492##                                                                          382 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 0.9-1.4(m,5H),                            1.6-1.8(m,6H), 2.0- 2.3(m,3H), 2.3-2.6(m,3H),                                 3.1-3.2(m,1H), 3.3-3.4 (m,2H), 3.5-3.6(m,1H),                                 4.95-5.1(m,2H), 5.2-5.45(m,1H), 7.1(d,1H), 7.25-7.4(m,2H)                     ppm.                                                           144.sup.2                                                                        3 #STR493##                                                                          416 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 1.25-1.6(m,2H),                           1.6-1.9(m,5H), 1.95- 2.3(m,5H), 2.3-2.6(m,3H),                                3.2-3.3(m,1H), 3.3-3.4 (m,2H), 3.5-3.55(m,1H),                                4.9-5.05(m,2H), 5.3-5.45 (m,1H), 7.05-7.2(m,1H),                              7.3-7.45(m,2H) ppm.                                            __________________________________________________________________________     Footnotes:                                                                    .sup.1 Bromoalkane derivative used as the starting material.                  .sup.2 pToluenesulphonyloxyalkane derivative used as the starting             material.                                                                

Preparation 145 5(S)-5-Allyl-5-(3,4-dichlorophenyl)-2(1H)-piperidone

A solution of the compound of Preparation 146 (120 mg) in ethanol (5 ml)heated under reflux with concentrated sulphuric acid (0.4 ml) for twentyfour hours. The reaction was diluted with water (5 ml) and basifiedusing sodium carbonate. The solution was extracted with ethyl acetate(2×10 ml). The combined organic layers were dried using anhydrousmagnesium sulphate, filtered and the filtrate evaporated to drynessunder reduced pressure. The residue was chromatographed on silica geleluting with a solvent gradient of dichloromethane:methanol (100:0 to97:3 to 95:5, by volume) to give the title compound (10 mg). TLC R_(f)=0.4 (silica, dichloromethane: methanol, 95:5, by volume). LRMS m/z=284(m+1)⁺. [α]₅₈₉ ²⁵ =31.2° (c=0.00125).

¹ H-NMR (CDCl₃):δ=2.0-2.2 (m,3H), 2.3-2.5 (m,2H), 2.5-2.6 (m,1H), 3.4(d,1H), 3.6 (d,1H), 4.9-5.05 (m,2H), 5.25-5.4 (m,1H), 6.0 (s,br,1H),7.15-7.2 (m,1H), 7.4-7.5 (m,2H) ppm.

Preparation 1462-(3(S)-3-Aminomethyl-3-(3,4-dichlorophenyl)hex-S-en-1-yl)-4(S)-4-isopropyloxazolinehydrochloride

A solution of the compound of Preparation 147 (1 g, 1 mol. equiv.) indiethyl ether (200 ml) was added dropwise over one hour to a stirredsuspension of lithium aluminium hydride (3.7 g, 1 mol. equiv.) indiethyl ether (200 ml) under nitrogen at 0° C. The reaction was stirredfor one hour at 0° C. Water (3.7 ml) was added, followed by a 15% w/waqueous sodium hydroxide solution (3.7 ml) and further water (11.1 ml).The mixture was stirred for fifteen minutes, filtered and the filtrateevaporated to dryness under reduced pressure to give an oil which gave agelatinous gum on standing for eighteen hours. The gum was partitionedbetween ethyl acetate (200 ml) and 2N aqueous hydrochloric acid solution(100 ml). The organic portion was separated, dried using anhydrousmagnesium sulphate, filtered and the solvent evaporated from thefiltrate under reduced pressure. The resultant solid was chromatographedon silica gel eluting with a solvent gradient ofdichloromethane:methanol (100:0 to 95:5 to 90:10, by volume) to give thetitle compound (21.4 g). LRMS m/z=369(m)⁺.

¹ H-NMR (CDCl₃):δ=0.7-0.8 (m,3H), 0.9-1.0 (m,3H), 1.6-1.8 (m,1H),1.95-2.2 (m,3H), 2.2-2.4 (m,1H), 2.4-2.55 (m,1H), 2.8-3.0 (m,1H),3.3-3.5 (m,2H), 3.6-4.0 (m,3H), 4.9-5.1 (m,2H), 5.3-5.45 (m,1H), 7.1(d,1H), 7.3-7.7 (m,2H), 8.9 (d,br,1H), 9.4 (d,br,1H), 10.1 (s,br,1H)ppm.

Preparation 1472-(3(S)-3-Cyano-3-(3,4-dichlorophenyl)hex-5-en-1-yl)-4(S)-4-isopropyloxazoline

A solution of the compound of Preparation 148 (3 g, 1 mol. equiv.) andS-valinol (1.04 g, 1 mol. equiv.) in toluene (30 ml) was heated underreflux under Dean-Stark conditions for eighteen hours. More toluene wasthen added and the reaction heated under reflux for a further fortyeight hours. The toluene was then removed by evaporation under reducedpressure and the residue chromatographed on silica gel eluting with asolvent gradient of hexane:diethyl ether (100:0 to 80:20 to 60:40, byvolume) to give the title compound (1 g). LRMS m/z=365(m)⁺.

¹ H-NMR (CDCl₃):δ=0.8 (d,3H), 0.95 (m,3H), 1.6-1.8 (m,1H), 2.05-2.3(m,2H), 2.4-2.55 (m,2H), 2.6-2.8 (m,2H), 3.8-4.0 (m,2H), 4.15-4.2(m,1H), 5.1-5.2 (m,2H), 5.5-5.7 (m,1H), 7.2-7.25 (m,1H), 7.5-7.55 (m,2H)ppm.

REPARATION 148 4(S)-4-Cyano-4-(3,4-dichlorophenyl)hept-6-enoic acid

To a stirred solution of the compound of Preparation 149 (5.5 g) indichloromethane (100 ml) was added 1N aqueous hydrochloric acid solution(100 ml). The aqueous layer was then removed and the organic portionwashed with 1 N aqueous hydrochloric acid solution (70 ml). The organiclayer was dried using anhydrous magnesium sulphate, filtered, and thefiltrate evaporated to dryness under reduced pressure to give the titlecompound (3.6 g). LRMS m/z=316(m+NH₄)⁺.

¹ H-NMR (CDCl₃):δ=2.15-2.8 (m,6H), 5.1-5.25 (m,2H), 5.55-5.7 (m,1H),7.2-7.25 (m,1H), 7.5-7.55 (m,2H) ppm.

Preparation 149 4(S)-4-Cyano-4-(3,4-dichlorophenyl)hept-6-enoic acid(R)-(+)-1-(1-naphthyl)ethylamine salt

To a solution of the compound of Preparation 150 (16 g) in ethyl acetate(50 ml) was added R-(+)-1-(1-naphthyl)ethylamine (4.8 g). The solutionwas stirred for thirty minutes at room temperature and then the solventremoved under reduced pressure to give a gum. This gum was partiallydissolved in hexane:diethyl ether (4:1, by volume, 150 ml) and the sidesof the flask scratched to induce crystallisation. The white solid thatformed was filtered off and cystallised three times from ethyl acetateto give the title compound (4.9 g). m.p. 153-154° C. [α]₅₈₉ ²⁵ -7.1°(c=0.0012).

¹ H-NMR (CDCl₃):δ=1.6 (d,3H), 2.0-2.2 (m,2H), 2.25-2.5 (m,2H), 2.5-2.7(m,2H), 3.8-4.1 (s,br,3H), 5.0-5.2 (m,3H), 5.5-5.7 (m,1H), 7.15-7.25(m,1H), 7.4-7.6 (m,6H), 7.75 (d,1H), 7.9 (d,1H), 8.1 (d,1H) ppm.

Preparation 150 4-Cyano-4-(3,4-dichlorophenyl)hept-6-enoic acid

To a stirred suspension of 60% w/w sodium hydride oil dispersion (231 g)in tetrahydrofuran (17L) under nitrogen at -10° C. was added a solutionof 3-bromopropanoic acid (806.5 g) in tetrahydrofuran (6L) dropwise overthree hours. The reaction was allowed to warm to room temperature over22 hours. The reaction was then cooled to -10° C. Simultaneously, asolution of the compound of Preparation 151 (1633.5 g) intetrahydrofuran (2.5L) was added dropwise over two hours to a stirredtetrahydrofuran suspension (2.5L) of 60% w/w sodium hydride oildispersion (221 g) in tetrahydrofuran (2.5L) under nitrogen at -10° C.When the addition was complete, this second reaction was allowed to warmto room temperature over eighteen hours. This reaction was then cooledto -10° C. and cannulated into the above 3-bromopropanoic acid sodiumsalt mixture over 3 hours. The reaction mixture was heated at 50° C. forfive hours. The reaction was then cooled, poured into water (8L) andbasified to pH 9.3 using aqueous sodium bicarbonate solution. Thismixture was washed with dichloromethane (5×2L) and the aqueous portionacidified to pH 1.0 using concentrated hydrochloric acid. The aqueoussolution was extracted with dichloromethane (4×2.5L) and the organiclayers were combined, dried using anhydrous magnesium sulphate, filteredand the filtrate concentrated under reduced pressure to give a yellowoil. This oil was then triturated with hexane (1.5L) to give the titlecompound as a cream solid (1155.3 g) which was used without any furtherpurification. TLC R_(f) =0.42 (silica, methanol:dichloromethane, 1:9, byvolume). LRMS m/z=316(m+NH₄)⁺.

¹ H-NMR (CDCl₃):δ=2.15-2.8 (m,6H), 5.1-5.25 (m,2H), 5.55-5.7 (m,1H),7.2-7.25 (m,1H), 7.5-7.55 (m,2H) ppm.

Preparation 151 2-(3,4-Dichlorophenyl)pent-4-enenitrile

To a stirred solution of 3,4-dichlorophenylacetonitrile (800 g, 4.3mol.) in cyclohexane (16L) at room temperature was carefully. addedaqueous sodium hydroxide solution (1600 g of sodium hydroxide in 8L ofwater). This addition caused an elevation of the reaction temperature to50° C. Allyl bromide (572 g, 1.1 mol. equiv.) and tetra-n-butylammoniumchloride hydrate (40 g, 0.03 mol. equiv.) were then added and thereaction stirred for one hour at 50° C. The aqueous phase was removedand the organic layer washed with water (10L). The organic phase wasfiltered through silica gel (1 kg) under reduced pressure to give ayellow filtrate solution. The solvent was removed from the filtrateunder reduced pressure to give the title compound as an oil (960 g) of70% purity which was used without any further purification. TLC R_(f)=0.71 (silica, diethyl ether:hexane, 1:1, by volume). LRMS m/z=226(m)⁺.

¹ H-NMR (CDCl₃):δ=2.6-2.75 (m,2H), 3.85 (t,1H), 5.1-5.25 (m,2H), 5.7-5.9(m,1H), 7.2-7.25 (m,1H), 7.5-7.55 (m,2H) ppm.

Preparation 152 1-(t-Butoxycarbonyl)-3-(piperazin-1-yl)azetidinemethanesulphonate

Piperazine (149.2 g, 8 mol. equiv.) was heated to a melt and1-(t-butoxycarbonyl)-3-methanesulphonyloxy-azetidine (see InternationalPatent Application Publication no. WO93/19059) (54.5 g, 217 mmol) wasthen added. The mixture was heated at 115° C. for twenty four hours. Thereaction was cooled and the excess piperazine removed under reducedpressure. The residue was purified by flash column chromatography onsilica gel using methanol:dichloromethane (5:95, by volume) as theeluant to give the title compound (51 g). LRMS m/z=242 (m+1)⁺.

¹ H-NMR (CDCl₃):δ=1.4 (m,9H), 2.5-2.6 (m,4H), 3.1-3.25 (m,5H), 3.7-3.8(m,2H), 3.9-3.95 (m,2H), 4.6 (br. s,1H) ppm.

Preparation 153 3-(4-Aminosulphonylpiperazin-1-yl)-1-(t-butoxycarbonylazetidine

A solution of the compound of Preparation 152 (50 g, 132.6 mmol) andsulphamide (88 g, 6.9 mol. equiv.) in 1,4-dioxane (1300 ml) was heatedunder reflux for fifty five hours. The solution was cooled and thesolvent removed under reduced pressure. The residue was purified byflash column chromatography on silica gel using methanol:dichloromethane (5:95, by volume) as the eluant to give the titlecompound (50 g).

¹ H-NMR (CDCl₃):δ=1.45 (s,9H), 2.4-2.5 (m,4H), 3.1-3.2 (m,1H), 3.25-3.3(m,4H), 3.75-3.8 (m,2H), 3.85-3.9 (m,2H), 4.3 (br. s,2H) ppm.

Preparation 154 3-(4-Aminosulphonylpiperazin-1-yl)azetidinebistrifluoroacetate

To a solution of the compound of Preparation 153 (364 mg, 1.14 mmol) indichloromethane (6 ml) under an atmosphere of nitrogen at 0° C. wasslowly added trifluoroacetic acid (3 ml, 35 mol. equiv.) and thereaction mixture was allowed to warm to room temperature over two hours.The solvent was then removed under reduced pressure and the residueazeotroped with dichloromethane (3×10 ml). The resulting oil wastriturated with diethyl ether to give the title compound (379 mg) whichwas used without further purification.

¹ H-NMR (CDCl₃):δ=2.4-2.6 (m,4H), 2.95-3.15 (m,4H), 3.35-3.5 (m,1H),3.8-4.1 (m,4H), 6.6-6.8 (m,2H), 8.6-8.85 (m,3H) ppm.

Preparation 155 1,1-Dicyclopropylethene

To a stirred suspension of methyltriphenylphosphonium bromide (133.5 g,3 mol. equiv.) in dimethylsulphoxide (200 ml) under nitrogen was added asolution of potassium tert-butoxide (42 g, 3 mol. equiv.) indimethylsulphoxide (200 ml), dropwise, over 15 minutes. Dicyclopropylketone (13.8 g, 0.125 mol.) was added and the solution heated at 60° C.for 1 hour and then stirred at room temperature for 16 hours. Thereaction was poured into 20% w/w aqueous sodium chloride solution (900ml) and ice (200 g) added. The mixture was extracted with diethyl ether(2 l) and the organic extract washed with water (2×1.5 l), dried usinganhydrous magnesium sulphate and filtered. The solvent was then removedfrom the filtrate under reduced pressure and the residue shaken with amixture of diethyl ether (50 ml) and hexane (50 ml). The mixture wasfiltered, the solvent removed from the filtrate under reduced pressureand the residue shaken with a mixture of hexane:diethyl ether (50 ml,9:1, by volume). The mixture was filtered and the solvent removed fromthe filtrate under reduced pressure to give the title compound (4.5 g).

¹ H-NMR (CDCl₃):δ=0.55-0.7(m,8H), 1.3-1.45(m,2H), 4.6(s,2H) ppm.

Preparation 156 2,2-Dicyclopropylethanol

To a solution of the compound of Preparation 155 (1 g, 9.24 mmol) intetrahydrofuran (15 ml) under nitrogen was added9-borabicyclo[3.3.1]nonane (18.5 ml of a 0.5M solution intetrahydrofuran, 1 mol. equiv.) and the solution stirred for 18 hours.Sodium hydroxide (3.08 ml of a 3M aqueous solution, 1 mol. equiv.) wasadded followed by ethanol (5 ml). The reaction was cooled to 5° C. andhydrogen peroxide (3.14 ml of a 30% w/w aqueous solution, 3 mol. equiv.)added. The reaction was stirred at room temperature for 1 hour.

The reaction was partitioned between ethyl acetate (50 ml) and water (50ml), the organic phase separated and dried using anhydrous magnesiumsulphate. The solution was filtered and the solvent removed from thefiltrate under reduced pressure to give an oil which was chromatographedon silica gel, eluting with diethyl ether:hexane (2:1, by volume) togive the title compound (160 mg).

¹ H-NMR (CDCl₃):δ=0.1-0.35(m,4H), 0.4-0.55(m,4H), 0.6-0.8 (m,2H),1.65(t,1H), 3.7(t,2H) ppm.

Preparation 157 2-Methanesulphonyloxyethylcyclopropane

The title compound was prepared by a similar method to that used inPreparation 13 except using 1.2 mole equivalents of triethylamine and1.3 mole equivalents of methanesulphonyl chloride. LRMS m/z=182(m+NH₄)⁺.

¹ H-NMR (CDCl₃):δ=0.1-0.15(m,2H), 0.5-0.55(m,2H), 0.7-0.8(m,1H),1.6-1.7(m,2H), 3.00(s,3H), 4.25-4.3(m,2H) ppm.

Preparation 158 2,2-Dicycloproryl-1-methanesulphonyloxyethane

To a solution of the compound of Preparation 156 (1 g, 7.9 mmol) indichloromethane (20 ml) at 5° C. under nitrogen was added triethylamine(1.32 ml, 1.2 mol. equiv.) followed by methanesulphonyl chloride (0.67ml, 1.1 mol. equiv.) and the reaction stirred for 2 hours. The solutionwas concentrated under reduced pressure and the residue partitionedbetween ethyl acetate (100 ml) and water (100 ml). The organic layer wasseparated, dried using anhydrous magnesium sulphate, filtered and thesolvent removed from the filtrate under reduced pressure. The residuewas chromatographed on silica gel eluting with diethyl ether:hexane(2:1, by volume) to give the title compound (1.5 g).

¹ H-NMR (CDCl₃):δ=0.1-0.15(m,4H), 0.2-0.3(m,5H), 0.35-0.4(m,2H),3.0(s,3H), 4.15(d,2H) ppm.

Preparation 159 N-Methylsulphamoyl chloride

To a solution of sulphuryl chloride (35.7 ml, 3 mol. equiv.) inacetonitrile (30 ml) under nitrogen was added methylamine hydrochloride(10 g, 148 mmol) followed by acetonitrile (30 ml). The reaction washeated under reflux for 20 hours. The reaction was cooled to roomtemperature and the mixture concentrated under reduced pressure to givethe title compound (20.51 g) which was used without furtherpurification.

¹ H-NMR (CDCl₃):δ=3.0(d,3H), 5.7(s,br.,1H) ppm.

Preparations 160 and 161

The compounds of the following tabulated preparations were prepared by asimilar method to that of Preparation 159 using sulphuryl chloride andthe appropriate amines.

    ______________________________________                                        Prep.             LRMS                                                        No.  Compound     m/z      Analysis/.sup.1 H-NMR                              ______________________________________                                        160  (CH.sub.3).sub.2 NSO.sub.2 Cl                                                              --       .sup.1 H-NMR(CDCl.sub.3): δ =                                           2.9(s,6H) ppm.                                     161                                                                                4 #STR494##  211 (m + 1).sup.+                                                                      .sup.1 H-NMR(CDCl.sub.3): δ = 3.3-                                      3.35(m,4H), 3.8-3.85 (m,4H) ppm.                   ______________________________________                                    

Preparation 162 Tert-butyl 6-bromohexanoate

To a solution of 6-bromohexanoic acid (9 g; 0.046 mol.) indichloromethane (50 ml) at -78° C. was added fuming sulphuric acid (0.5ml). To this solution was added liquid isobutylene (50 ml), dropwise.The reaction was allowed to warm to room temperature and stirred for 18hours.

The mixture was poured into ice-cooled saturated aqueous sodiumcarbonate solution. The mixture was extracted with dichloromethane (2×40ml), and the combined extracts washed with brine (40 ml). The organiclayer was dried using magnesium sulphate. The mixture was filtered andthe solvent removed from the filtrate under reduced pressure to providethe title compound as a yellow oil which was used with furtherpurification. TLC Rf=0.25 (silica, methanol: dichloromethane, 1:9, byvolume). LRMS m/z=267.8(m+18)⁺.

¹ H-NMR (CDCl₃):δ=1.3-1.45(m,11H), 1.45-1.6(m,2H), 1.7-1.85(m,2H),2.15(t,2H), 3.35(t,2H) ppm.

Preparation 163 4-(2-Benzoxazolyl)piperidine

A mixture of 2-aminophenol (20 g, 183 mmol), isonipecotic acid (23.7 g,1 mol. equiv.) and polyphosphoric acid (50 ml) was heated together for 2hours with stirring. The reaction mixture was cooled, poured onto ice(400 g) and solid sodium hydroxide (85 g) added until the solutionachieved pH8. The solid was filtered off, slurried in water (500 ml) andfiltered to give the title compound (4.5 g).

A second crop of the title compound was obtained by extracting the abovefiltrate with dichloromethane (4×200 ml). The combined organic extractswere dried using anhydrous magnesium sulphate, filtered and the solventremoved from the filtrate under reduced pressure to give the titlecompound (9 g).

¹ H-NMR (CDCl₃):δ=1.9-2.1 (m,3H), 2.15-2.3(m,2H), 2.8-2.9(m,2H),3.1-3.3(m,3H), 7.3-7.35(m,2H), 7.5-7.55(m, 1H), 7.7-7.75(m,1H) ppm.

Preparation 164 1-Benzyl-4-(tert-butoxycarbonylamino)piperidine

To a solution of 4-amino-1-benzylpiperidine (10 g, 53 mmol) indichloromethane (200 ml) at 0° C. was added di-tert-butyl dicarbonate(12.6 g, 1.1 mol. equiv.) and the mixture stirred a t room temperaturefor 16 hours.

The crude reaction mixture was washed with 2% w/w aqueous sodiumbicarbonate solution (300 ml), dried using anhydrous magnesium sulphateand the solution filtered. Removal of the solvent from the filtrateunder reduced pressure gave a beige solid which was purified by columnchromatography on silica gel eluting with dichloromethane:methanol(95:5, by volume) to give the title compound (13.1 g). TLC Rf=0.3(dichloromethane:methanol, 95:5, by volume).

¹ H-NMR (CDCl₃):δ=1.35-1.5(m,11H), 1.85-1.95(m,2H), 2.05-2.15(m,2H ),2.75-2.8(m,2H), 3.4-3.5(m,3H), 4.4(s,br., 1H), 7.2-7.3(m,5H) ppm.

Preparation 165 4-(Tert-butoxycarbonylamino)piperidine

To a solution of the compound of Preparation 164 (13.1 g, 45.1 mmol) inethanol (135 ml) was added 10% w/w palladium-on-carbon (0.6 g) and themixture stirred under an atmosphere of hydrogen at 414 kPa (60 p.s.i.)for 16 hours. After this time, a further 0.6 g of the catalyst was addedand the mixture stirred under an atmosphere of hydrogen at 414 kPa (60p.s.i.) for a further 72 hours. The reaction mixture was then filteredthrough a cellulose-based filter aid and the filtrate concentrated underreduced pressure to give a solid. This was triturated with diethyl ether(50 ml), filtered and the solid obtained dried under reduced pressure togive the title compound (8.1 g).

¹ H-NMR (CDCl₃):δ=1.15-1.3(m,2H), 1.35-1.5(m,10H), 1.9-1.95(m,2H),2.6-2.7(m,2H), 3.0-3.1 (m,2H), 3.5(s,br., 1H), 4.4(s,br., 1H) ppm.

Preparation 166 1-Benzyloxycarbonyl-4-hydroxypiperidine

To a solution of 4-hydroxypiperidine (4.2 g, 41 mmol) in dichloromethane(50 ml) at 0° C. under an atmosphere of nitrogen was slowly added benzylchloroformate (7.7 ml, 1.3 mol. equiv.) followed by triethylamine (6.94ml, 1.2 mol. equiv.). The reaction was stirred at room temperature for15 hours.

The reaction was washed with saturated sodium bicarbonate solution (2×50ml) and the organic layer dried using anhydrous magnesium sulphate,filtered and the filtrate evaporated under reduced pressure to dryness.The crude product was purified by flash chromatography on silica geleluting with methanol:dichloromethane (1:20, by volume) to give thetitle compound (9.24 g). TLC Rf=0.68 (silica, methanol:dichloromethane,1:10, by volume). LRMS m/z=236 (m+1)⁺.

¹ H-NMR (CDCl₃):δ=1.35-1.55(m,2H), 1.75(m,1H), 1.8-2.0(m,2H),3.1-3.2(m,2H), 3.8-4.0(m,3H), 5.15(s,2H), 7.35(s,5H) ppm.

Preparation 167 1-Benzyloxycarbonyl-(4-tert-butyloxy)piperidine

To a solution of the compound of Preparation 166 (9.24 g) incyclohexane: dichloromethane (120 ml, 3:1, by volume) at 0° C. under anitrogen atmosphere was added t-butyl trichloroacetimidate (14.1 ml, 2mol. equiv.) and boron trifluoride etherate (0.8 ml, 0.16 mol. equiv.).The reaction was allowed to warm to room temperature and stirred for 48hours.

The solvent was removed from the reaction by evaporation under reducedpressure. The reaction was taken up in ethyl acetate (50 ml) and washedwith saturated sodium bicarbonate solution (30 ml). The aqueous layerwas extracted with ethyl acetate (2×30 ml). The organic layers werecombined, dried using anhydrous magnesium sulphate, filtered and thefiltrate evaporated under reduced pressure to dryness. The residue wasthen purified by flash column chromatography on silica gel eluting withmethanol:dichloromethane (3:97 by volume), followed by flash columnchromatography for a second time on silica gel eluting withmethanol:dichloromethane (1:5, by volume). This gave the title compound(9 g). TLC Rf=0.56 (silica, methanol:dichloromethane, 1:20, by volume).LRMS m/z=292 (m+1)⁺.

¹ H-NMR (CDCl₃):δ=1.2(s,9H), 1.4-1.55(m,2H), 1.65-1.8(m,2H),3.1-3.25(m,2H), 3.6-3.7(m,1H), 3.8-4.0(m,2H), 5.15(s,2H), 7.4(s,5H) ppm.

Preparation 168 4-(Tert-butyloxy)piperidine

The compound of Preparation 167 (8.41 g, 28.8 mmol) was dissolved inethanol (100 ml) and 10% w/w palladium-on-carbon (0.34 g) added. Themixture was stirred under hydrogen at 414 kPa (60 p.s.i.) for 24 hours.The catalyst was filtered off and the solvent removed from the filtrateunder reduced pressure. The resulting oil has purified by columnchromatography on silica gel eluting with concentrated aqueous ammoniasolution:methanol:dichloromethane (1:10:89, by volume) to give the titlecompound (2.48 g). TLC Rf=0.23 (silica, concentrated aqueous ammoniasolution:methanol:dichloromethane 1:10:89, by volume). LRMS m/z=158(m+1)⁺.

Preparation 169 1-(Tert-butoxycarbonyl)-3-(1-piperazinyl)azetidine

Piperazine (23.69 g, 8 mol. equiv.) was melted and1-(t-butoxycarbonyl)-3-methanesulphonyloxyazetidine (see InternationalPatent Application Publication no. WO93/19059) (8.64 g, 34.4 mmol)added. The mixture was heated at 120° C. for 15 hours under nitrogen.The reaction was cooled to room temperature and the excess piperazineremoved under reduced pressure. The residue was then chromatographed onsilica gel using gradient elution (methanol:dichloromethane 1:19changing to 1:4, by volume) to give the title compound (6.32 g). LRMSm/z=242 (m+1)⁺.

¹ H-NMR (d₆ -DMSO):δ=1.35(s,9H), 2.4-2.5(m,4H), 3.0-3.1(m,5H), 3.2-4.2(m,br.,5H) ppm.

Preparation 1701-(Tert-butoxycarbonyl)-3-(4-methylsulphonylpiperazin-1-yl)azetidine

To a solution of the compound of Preparation 169 (8.06 g, 21.3 mmol) indichloromethane (160 ml) was added triethylamine (13.4 ml). The solutionwas kept under a nitrogen atmosphere and cooled to 0° C.Methanesulphonyl chloride (5.25 ml, 7.77 g, 3 mol. equiv.) was added,dropwise, over 30 minutes. The reaction was allowed to warm to roomtemperature over 2.5 hours and then stirred for a further 18 hours. Thereaction was washed with water (3×50 ml) and then brine (2×30 ml). Theorganic layer was dried using anhydrous magnesium sulphate. The mixturewas then filtered and the solvent removed from the filtrate underreduced pressure. The residue was chromatographed on silica gel elutingwith concentrated aqueous ammonia:methanol:dichloromethane (1:10:89, byvolume). The product from this chromatography step was then columnchromatographed again on silica gel eluting with methanol:ethyl acetate(1:10, by volume) to give the title compound (0.9 g). TLC Rf=0.6(silica, concentrated aqueous ammonia solution:methanol:dichloromethane,1:10:89 by volume). LRMS m/z=320 (m+1 )⁺.

¹ H-NMR (CDCl₃):δ=1.4(s,9H), 2.45(t,4H), 3.8(s,3H), 3.1-3.2(m,1H),3.2-3.3(m,4H), 3.75-3.8(m,2H), 3.9-4.0(m,2H) ppm.

Preparation 1713-(4-Benzoylpiperazin-1-yl)-1-(tert-butoxycarbonyl)azetidine

To a solution of the compound of Preparation 169 (3.3 g) indichloromethane (70 ml) at room temperature under nitrogen was addedtriethylamine (4.06 ml) and benzoyl chloride (2.30 ml). The mixture wasallowed to stir at room temperature for 16 hours. The reaction mixturewas washed with water (3×100 ml) and brine (3×100 ml), dried usinganhydrous magnesium sulphate, filtered and the solvent removed from thefiltrate under reduced pressure. The residue was column chromatographedon silica gel eluting with ethyl acetate to yield the title compound(2.3 g).

Preparation 1721-(Tert-butoxycarbonyl)-3-(4-methylcarbamoylpiperazin-1-yl)azetidine

To a solution of the compound of Preparation 169 (3.3 g) indichloromethane (70 ml) was added methyl isocyanate and the mixtureallowed to stir at room temperature for 72 hours. After this time, thedichloromethane was removed by bubbling nitrogen through the solution.The residue was taken up in dichloromethane (100 m) and washed with 10%w/w aqueous sodium bicarbonate solution (100 ml) followed by brine (100ml). The organic layer was dried using anhydrous magnesium sulphate,filtered and the solvent removed from the filtrate under reducedpressure. The residue was chromatographed on silica gel eluting withdichloromethane:methanol (95:5, by volume) to give the title compound(1.8 g). LRMS m/z=299 (m+1)⁺.

¹ H-NMR (CDCl₃):δ=1.40(s,9H), 2.25-2.35(m,4H), 2.8-2.85(m,3H), 3.0-3.1(m, 1H), 3.35-3.4(m,4H), 3.75-3.85(m,2H), 3.9-3.95(m,2H), 4.4(s,br., 1H)ppm.

Preparation 1731-(Tert-butoxycarbonyl)-3-(4-methylaminosulphonylpiperazin-1-yl)azetidine

To a solution of the compound of Preparation 169 (500 mg, 2.07 mmol) inacetonitrile (5 ml) under nitrogen was added triethylamine (0.43 ml, 1.5mol. equiv.). A solution of the compound of Preparation 159 (295 mg, 1.1mol. equiv.) in acetonitrile (2 ml) was added, dropwise, and thereaction heated at 90° C. for 3 hours. The reaction was cooled to roomtemperature and the solvent removed under reduced pressure. The residuewas partitioned between ethyl acetate (50 ml) and water (50 ml). Theorganic layer was separated and washed with brine (50 ml), dried usinganhydrous magnesium sulphate, filtered and the solvent removed from thefiltrate under reduced pressure. The residue was chromatographed onsilica gel eluting with methanol:dichloromethane (1:19, by volume) togive the title compound (374 mg). TLC Rf=0.73 (silica, methanol:dichloromethane, 1:9, by volume). LRMS m/z=335(m+1)⁺.

¹ H-NMR (CDCl₃):δ=1.4(s,9H), 2.4-2.45(m,4H), 2.7-2.75(m,3H),3.1-3.15(m,1H), 3.25-3.3(m,4H), 3.75-3.9(m,4H), 4.15-4.2(m,1H) ppm.

Preparations 174 and 175

The compounds of the following tabulated Preparations of the generalformula: ##STR495## were prepared by a similar method to that ofPreparation 173 using the same piperazine starting material togetherwith the appropriate sulphamoyl chlorides (see Preparations 160 and161).

    __________________________________________________________________________    Prep.               LRMS                                                      No.                                                                              --X.sup.1 --R.sup.2                                                                            m/z  Analysis/.sup.1 H-NMR                                __________________________________________________________________________    174                                                                              5 #STR496##      349 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 1.45(s,9H),                               2.4(m,4H), 2.85(m,6H), 3.1-3.2(m,1H),                                         3.3-3.35(m,4H), 3.75-3.95(m,4H) ppm.                 175                                                                              6 #STR497##      391 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 1.45(s,9H),                               2.4-2.45 (m,4H), 3.1-3.15(m,1H), 3.2-3.35(m,8H),                              3.7- 3.95(m,8H) ppm.                                 __________________________________________________________________________

Preparation 1761-(Tert-butoxycarbonyl)-3-(4-methoxypiperidin-1-yl)azetidine

To a solution of the compound of Preparation 71 (1 g, 4.12 mmol) intetrahydrofuran (12 ml) at 0° C. under nitrogen, was added, in twoportions, 60% w/w sodium hydride/dispersion in oil (0.198 mg, 1.2 mol.equiv.). After 30 minutes stirring, methyl iodide (0.282 ml, 1.1 mol.equiv.) was added and the mixture stirred for 16 hours.

The solvent was removed under reduced pressure and the residuepartitioned between ethyl acetate (50 ml) and saturated aqueous sodiumbicarbonate solution (50 ml). The organic layer was separated and driedusing anhydrous sodium sulphate. The mixture was filtered and thesolvent removed from the filtrate under reduced pressure to give an oil.This crude product was purified by column chromatography on silica geleluting with methanol:dichloromethane (3:97, by volume) to give thetitle compound as a colourless oil (0.84 g). TLC Rf=0.2 (silica,methanol:dichloromethane, 3:97, by volume).

¹ H-NMR (CDCl₃):δ=1.4(m,9H), 1.55-1.7(m,2H), 1.8-2.0(m,2H),2.0-2.15(m,2H), 2.55-2.65(m,2H), 3.0-3.1 (m, 1H), 3.2-3.3(m, 1H),3.35(s,3H), 3.75-3.8(m,2H), 3.9-4.0(m,2H) ppm.

Preparations 177 and 178

The compounds of the following tabulated Preparations of the generalformula: ##STR498## were prepared using a similar method to that ofPreparation 176 using the same piperidinol starting material and ethyliodide or n-propyl iodide, as appropriate, as the alkylating agent.

    __________________________________________________________________________    Prep.              LRMS                                                       No.                                                                              --X.sup.1 --R.sup.2                                                                           m/z  Analysis/.sup.1 H-NMR                                 __________________________________________________________________________    177                                                                              7 #STR499##     --   .sup.1 H-NMR(CDCl.sub.3): δ = 1.2(t,3H),                                1.4(s,9H), 1.55- 1.7(m,2H), 1.8-1.95(m,2H),                                   1.95-2.1(m,2H), 2.5- 2.7(m,2H), 3.0-3.1(m,1H),                                3.3-3.4(m,1H), 3.5 (q,2H), 3.75-3.8(m,2H),                                    3.9-3.95(m,2H) ppm.                                   178                                                                              8 #STR500##     299.2 (m + 1).sup.+                                                                --                                                    __________________________________________________________________________

Preparation 179 3-(4-Benzoylpiperazin-1-yl)azetidine bistrifluoroacetate

To a solution of the compound of Preparation 171 (2.3 g) indichloromethane (18 ml) at 0° C. under nitrogen was addedtrifluoroacetic acid (9 ml), dropwise, and the mixture allowed to stirat room temperature for 1 hour. The solvent was carefully removed byevaporation under reduced pressure and the residue azeotroped withdichloromethane (3×20 ml). The resulting oil was washed with diethylether (3×20 ml). Ethyl acetate (50 ml) was then added and theprecipitate collected by filtration and dried to give the title compound(132 mg). A second crop of the title compound (186 mg) was obtained byconcentration of the filtrate under reduced pressure to give an oil.This was triturated with diethyl ether and ethyl acetate and the solidobtained collected by filtration and dried to give the title compound(0.32 g).

¹ H-NMR (d₆ -DMSO):δ=2.3-2.45(m,4H), 3.3-3.7(m,5H), 3.8-4.05(m,5H),7.3-7.4(m,5H), 8.65(s,br.,1H) ppm.

Preparation 180 3-(4-Methoxycarbonylpiperidin-1-yl)azetidinedihydrochloride

To a solution of the compound of Preparation 105 (7.5 g, 19.81 mmol) indichloromethane (100 ml) at 0° C. under nitrogen was added α-chloroethylchloroformate (2.6 ml, 1.2 mol. equiv.) and the reaction warmed to roomtemperature over 1 hour. Methanol (150 ml) and potassium carbonate (8.2g, 3 mol. equiv.) were then added and the reaction heated under refluxfor 3 hours.

The reaction was cooled to room temperature, filtered and the filtrateacidified to pH3 with methanolic hydrogen chloride. The mixture wasfiltered and the solvent removed by evaporation under reduced pressure.The residue was washed with diethyl ether (3×100 ml) and then trituratedwith diethyl ether to give a solid that was filtered off and dried toyield the title compound (5.1 g). LRMS m/z=199 (m+1)⁺.

Preparation 181 3-(4-Tert-butoxycarbonylaminopiperidin-1-yl)azetidinebistrifluoroacetate

To a solution of the compound of Preparation 106 (6.8 g, 16.1 mmol) indichloromethane (70 ml) at 0° C. under nitrogen was addedalpha-chloroethyl chloroformate (1.91 ml, 1.1 mol. equiv.) and themixture stirred at room temperature for 1 hour. After this time, thesolvent was removed by evaporation under reduced pressure, the residuedissolved in methanol (80 ml) and potassium carbonate (4.9 g, 2.2 mol.equiv.) added. The mixture was then heated under reflux for 1 hour. Thereaction mixture was cooled to room temperature, filtered and thefiltrate acidified to pH5 by the dropwise addition of trifluoroaceticacid. The solvent was removed under reduced pressure to give a gum whichwas triturated with diethyl ether to give a solid. This solid wascollected by filtration and dried under reduced pressure to give thetitle compound as a crude product that was used directly.

Preparation 1825(S)-5-(3,4-Dichlorophenyl)-1-(4,4-difluorocyclohexylmethyl)-5-(1,3-dioxolan-2-ylmethyl)-2-piperidone

To a stirred mixture of dimethyl sulphoxide (50 ml) and potassiumhydroxide (2.1 g) at room temperature under nitrogen was added asolution of the compound of Example 123(b) (3 g, 9.1 mmol) in dimethylsulphoxide (50 ml) followed by the compound of Preparation 11 (3.1 g)and the mixture stirred at room temperature for 16 hours. Water (300 ml)and brine (300 ml) were added and the mixture extracted with ethylacetate (3×300 ml). The combined organic extracts were washed with brine(300 ml), dried using anhydrous magnesium sulphate, filtered and thesolvent removed from the filtrate by evaporation under reduced pressure.The residue was chromatographed on silica gel eluting with a solventgradient of ethyl acetate:hexane (1:1 changing to 7:3 changing to 4:1changing to neat ethyl acetate) to give the title compound (3.3 g). LRMSm/z=462 (m+1)⁺.

¹ H-NMR (CDCl₃):δ=1.3-1.45(m,2H), 1.6-1.95(m,6H), 2.1-2.2(m,6H),2.4-2.55 (m, 1H), 3.2-3.3(m, 1H), 3.4-3.5(m,2H), 3.65-3.75(m,3H),3.85-3.95(m,2H), 4.3-4.35(m,1H), 7.1-7.4(m,3H) ppm.

Preparations 183 to 186

The compounds of the following tabulated Preparations of the generalformula: ##STR501## were prepared by a similar method to that ofPreparation 182 using the appropriate piperidone (see Example 123(b) andPreparation 193) and the appropriate mesylate starting materials forPreparations 183 and 184 and the appropriate bromide starting materialsfor Preparations 185 and 186.

    __________________________________________________________________________    Prep.             LRMS                                                        No.                                                                              R           m.p.                                                                             m/z  Analysis/.sup.1 H-NMR                                  __________________________________________________________________________    183.sup.1                                                                        9 #STR502## -- 398 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 0.1-0.15(m,2H),                            0.45- 0.5(m,2H), 0.6-0.75(m,1H), 1.5-1.6(m,2H),                              1.9- 1.95(m,1H), 2.1-2.2(m,4H), 2.35-2.5(m,1H),                               3.3- 3.4(m,1H), 3.5-3.6(m,1H), 3.65-3.75(m,4H),                               3.85-3.9(m,2H), 4.35-4.4(m,1H), 7.1-7.45(m,3H)                                ppm.                                                   184.sup.1                                                                        0 #STR503## -- 438 (m + 1).sup.+                                                                  .sup.1 H-NMR(CDCl.sub.3): δ = 0.1-0.25(m,4H),                            0.35- 0.55(m,4H), 0.6-0.7(m,3H), 1.9-2.5(m,6H),                              3.15- 3.2(m,1H), 3.55-3.95(m,7H), 4.35-4.4(m,1H),                             7.1-7.4(m,3H) ppm.                                     185.sup.1                                                                        --CH.sub.2 (CH.sub.2).sub.4 CO.sub.2 C(CH.sub.3).sub.3                                    -- 500 (m).sup.+                                                                      .sup.1 H-NMR(CDCl.sub.3): δ = 1.3-1.4(m,2H),                            1.4(s,9H), 1.55-1.7(m,5H), 2.0-2.5(m,6H),                                     3.2-3.3(m,1H), 3.4-3.6(m,2H), 3.7-3.8(m,3H),                                  3.85-3.95(m,2H), 4.3-4.4(m,2H), 7.05(d,1H),                                   7.3(d,1H), 7.4(d,1H) ppm.                              186.sup.2                                                                        1 #STR504## -- --   .sup.1 H-NMR(CDCl.sub.3): δ = 0.3-0.4(m,2H),                            0.55-0.65 (m,2H), 1.05-1.15(m,1H), 1.9-1.95(m,1H),                            2.0- 2.25(m,4H), 2.35-2.45(m,1H), 3.15-3.2(m,1H),                             3.5-3.55(m,2H), 3.65-3.75(m,2H), 3.9-4.0 (m,3H),                              4.35-4.4(m,1H), 7.2-7.5(m,3H), ppm.                    __________________________________________________________________________     Footnotes:-                                                                   .sup.1 (S)enantiomer prepared                                                 .sup.2 (R)enantiomer prepared.                                           

Preparation 1875(S)-5-(3,4-Dichlorophenyl)-5-formylmethyl-2(1H)-piperidone

A solution of the compound of Example 123(b) (280 mg, 0.85 mmol) intetrahydrofuran (3 ml) and 5N aqueous hydrochloric acid solution (3 ml)was stirred at room temperature under nitrogen for 4 hours. The reactionwas poured into a mixture of ethyl acetate (20 ml) and saturated aqueoussodium bicarbonate solution (20 ml). The organic phase was separated,dried using anhydrous magnesium sulphate, filtered and the solventremoved by evaporation under reduced pressure to give the title compound(283 mg) which was used without further purification. TLC Rf=0.26(silica, methanol:dichloromethane, 1:9, by volume).

Preparations 188 to 191

The compounds of the following tabulated Preparations of the generalformula: ##STR505## were prepared by a similar method to that ofPreparation 187 using the appropriate dioxolane starting materials (seePreparations 183 to 186).

    __________________________________________________________________________    Prep.              LRMS                                                       No. R           m.p.                                                                             m/z  Analysis/.sup.1 H-NMR                                 __________________________________________________________________________    188.sup.1,4                                                                       2 #STR506## -- 354 (m + 1).sup.+                                                                  --                                                    189.sup.2,4                                                                       3 #STR507## -- --   .sup.1 H-NMR(CDCl.sub.3): δ = 0.1-0.25(m,4H)                            , 0.35- 0.5(m,4H), 0.55-0.7(m,3H), 2.1-2.3(m,3H),                             2.35- 2.5(m,1H), 2.7-2.75(m,1H), 2.9-2.95(m,1H),                              3.15-3.25(m,1H), 3.6-3.9(m,3H), 7.1-7.45 (m,3H),                              9.5(m,1H) ppm.                                        190.sup.4                                                                         --CH.sub.2 (CH.sub.2).sub.4 CO.sub.2 C(CH.sub.3).sub.3                                    -- 456  .sup.1 H-NMR(CDCl.sub.3): δ = 1.3-1.4(m,2H),                             1.4(s,9H),                                                              (m).sup.+                                                                          1.55-1.7(m,5H), 2.1-2.25(m,5H), 2.3-                                          2.45(m,1H), 2.7(d,1H), 2.95(d,1H), 3.2-3.35                                   (m,1H), 3.4-3.6(m,2H), 3.75(d,1H), 7.05(d,1H),                                7.3(d,1H), 7.4(d,1H), 9.45(s,1H) ppm.                 191.sup.3                                                                         4 #STR508## -- --   .sup.1 H-NMR(CDCl.sub.3): δ = 0.25-0.35(m,2H                            ), 0.55- 0.65(m,2H), 1.05-1.1(m,1H),                                          2.15-2.25(m,3H), 2.35-2.5(m,1H), 2.65-2.75(m,1H),                             2.95-3.05 (m,1H), 3.15-3.2(m,1H), 3.45-3.6(m,2H),                             3.95- 4.0(m,1H), 7.2-7.45(m,3H), 9.5(s,1H)            __________________________________________________________________________                            ppm.                                                   Footnotes:-                                                                   .sup.1 Product contaminated with ca. 35% of the dioxolane starting            material by .sup.1 HNMR spectroscopy.                                         .sup.2 Product contaminated with ca. 6% of the dioxolane starting materia     by .sup.1 HNMR spectroscopy.                                                  .sup.3 (R)enantiomer prepared.                                                .sup.4 (S)enantiomer prepared.                                           

Preparation 1924(R)-4-Cyano-4-(3,4-dichlorophenyl)-5-(1,3-dioxolan-2-yl)pentan-1-oicacid

The filtrate taken from the fractional crystallisation of the(S)-(-)-alpha-methylbenzylamine salts of 4(R)- and4(S)-4-cyano-4-(3,4-dichlorophenyl)-5-(1,3-dioxolan-2-yl)pentan-1-oicacid (see Example 123(a)) was evaporated to dryness under reducedpressure to provide a solid (800 g). This solid was dissolved in methylethyl ketone (3 l) and water (300 ml) by heating under reflux. Furthermethyl ethyl ketone (1 l) was added and the mixture cooled. A pure seedcrystal of the required compound was added. No crystallisation occurred.The solution was therefore reduced to half-volume by evaporation underreduced pressure. The mixture was left to stand for 72 hours to providea solid which was filtered off and washed with methyl ethyl ketone(2×200 ml). This white solid was dried at 35° C. for 3 hours underreduced pressure and then dissolved in methyl ethyl ketone (1.5 l) andwater (165 ml). The solution was heated under reflux for 1 hour. Methylethyl ketone (700 ml) was added and the mixture again seeded with therequired compound and left to stand for 56 hours. The resulting solidwas filtered off and washed with methyl ethyl ketone (2×100 ml), thendried under reduced pressure at 35° C. for 4 hours to give the(S)-(-)-alpha-methylbenzylamine salt of the title compound (133 g). HPLC(Ultron ES-OVM column, mobile phase=0.01M KH₂ PO₄ buffer at pH 6.6:acetonitrile, 92:8, by volume, flow rate=1 ml/min.) showed this salt tobe present in 98.4% e.e.

This salt was converted to the title compound by a similar method tothat described in Example 123(a) for its enantiomer.

¹ H-NMR (CDCl₃):δ=2.05-2.35(m,4H), 2.4-2.65(m,2H), 3.7-4.0(m,4H),4.75-4.85(m, 1H), 7.25-7.55(m,3H), 9.9(s,br., 1H,acid) ppm.

Preparation 193 5(R)-5-(3,4-Dichlorophenyl)-5-(1,3-dioxolan-2-ylmethyl)-2(1H)-piperidone

The title compound was prepared by a similar method to that used inExample 123(b) except the compound of Preparation 192 was used as thestarting material.

¹ H-NMR (CDCl₃):δ=1.85-1.95(m,1H), 2.0-2.25(m,4H), 2.35-2.4(m,1H),3.45-3.55(m, 1H), 3.65-3.75(m,2H), 3.8-3.9(m,3H), 4.35-4.4(m, 1H),6.15(s,br., 1H), 7.2-7.45(m,3H) ppm.

We claim:
 1. A compound of the formula: ##STR509## or a pharmaceuticallyacceptable salt thereof, wherein R is C₃ -C₇ cycloalkyl, aryl or C₁ -C₆alkyl, said C₁ -C₆ alkyl being optionally substituted by fluoro, --COOH,--COO(C₁ -C₄ alkyl), C₃ -C₇ cycloalkyl, adamantyl, aryl or het¹, andsaid C₃ -C₇ cycloalkyl being optionally substituted by 1 or 2substituents each independently selected from C₁ -C₄ alkyl, C₃ -C₇cycloalkyl, C₁ -C₄ alkoxy, hydroxy, fluoro, fluoro(C₁ -C₄)alkyl andfluoro(C₁ -C₄)alkoxy;R¹ is phenyl, naphthyl, thienyl, benzothienyl orindolyl, each optionally substituted by 1 or 2 substituents eachindependently selected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo andtrifluoromethyl; R² is --CO₂ H, --CONR³ R⁴, --CONR⁵ (C₃ -C₇ cycloalkyl),--NR⁵ (C₂ -C₅ alkanoyl), --NR³ R⁴, --NR⁵ CONR⁵ R⁶, (C₃ -C₇ cycloalkyl-C₁-C₄ alkyl)R⁵ N--, (C₃ -C₇ cycloalkyl-C₁ -C₄ alkyl)₂ N--, --NR⁵ COCF₃,--NR⁵ SO₂ CF₃, --NR⁵ (SO₂ C₁ -C₄ alkyl), --NR⁵ SO₂ NR⁵ R⁶, --NR⁵ (SO₂aryl), --N(aryl)(SO₂ C₁ -C₄ alkyl), --OR⁵, --O(C₃ -C₇ cycloalkyl), --SO₂NR⁵ R⁶, het³ or a group of the formula: ##STR510## R³ and R⁴ are eachindependently selected from H and C₁ -C₄ alkyl optionally substituted byhydroxy, C₁ -C₄ alkoxy, --S(O)_(p) (C₁ -C₄ alkyl), amino, --NH(C₁ -C₄alkyl), --N(C₁ -C₄ alkyl)₂ or het² ; R⁵ and R⁶ are each independentlyselected from H, C₁ -C₄ alkyl and C₃ -C₇ cycloalkyl-C₁ -C₄ alkyl, saidC₁ -C₄ alkyl and C₃ -C₇ cycloalkyl-C₁ -C₄ alkyl being optionallysubstituted by fluoro; R⁷ is H, C₁ -C₄ alkyl, hydroxy, fluoro(C₁-C₄)alkyl or phenyl, said phenyl being optionally substituted by 1 or 2substituents each independently selected from C₁ -C₄ alkyl, fluoro(C₁-C₄)alkyl, halo, C₁ -C₄ alkoxy and fluoro(C₁ -C₄)alkoxy; R⁸ is H,fluoro, hydroxy, C₁ -C₄ alkoxy, C₂ -C₅ alkanoyl or C₂ -C₅ alkanoyloxy;R⁹ is --NR⁵ R⁶, --NR⁵ COR⁵, --NR⁵ SO₂ CF₃, --NR⁵ (SO₂ C₁ -C₄ alkyl),--NR⁵ SO₂ NR⁵ R⁶, --NR⁵ COO(C₁ -C₄ alkyl), --NR⁵ CONR⁵ R⁶, --NR⁵ (SO₂morpholino), --NR⁵ (SO₂ aryl), --N(aryl)(SO₂ C₁ -C₄ alkyl) or a group ofthe formula: ##STR511## X is C₁ -C₄ alkylene; X¹ is a direct link or C₁-C₆ alkylene; X² is a direct link, CO, SO₂ or NR⁵ CO; W is methylene,CO, CH(OH), C(OH)₂, CH(C₁ -C₄ alkoxy), CHCO₂ H, CHCO₂ (C₁ -C₄ alkyl),CHCONR⁵ R⁶, CHF, CF₂, CH(azetidin-1-yl), CH(pyrrolidin-1-yl),CH(piperidin-1-yl), CH(morpholino), CH(benzoxazol-2-yl), CHR⁹, O,S(O)_(p), NR⁵, N(C₃ -C₇ cycloalkyl), NSO₂ (C₁ -C₄ alkyl), NSO₂ NR⁵ R⁶,NSO₂ CF₃, NSO₂ (morpholino), NSO₂ (aryl), ##STR512## NCONR⁵ R⁶, NCOR⁵,NCO(aryl) or NCO₂ (C₁ -C₄ alkyl); W¹ is methylene, CO, CH(OH), C(OH)₂,CH(C₁ -C₄ alkoxy), CHCO₂ H, CHCO₂ (C₁ -C₄ alkyl), CHCONR⁵ R⁶, CHF, CF₂,CH(azetidin-1-yl), CH(pyrrolidin-1-yl), CH(piperidin-1-yl),CH(morpholino) or CHR⁹ ; W² is W¹, --CH₂ W¹ --, --CH₂ WCH₂ -- or --CH₂CH₂ WCH₂ --; m is 0, 1 or 2; n is 1 or 2 when W is other than methyleneand is 0, 1 or 2 when W is methylene; p is 0, 1 or 2; q is 1 or 2; r is1, 2, 3 or 4; "aryl", used in the definition of R, R², R⁹ and W, meansnaphthyl or phenyl, each optionally substituted by C₁ -C₄ alkyl, halo,--OR⁵, fluoro(C₁ -C₄)alkyl, C₂ -C₅ alkanoyl, --CON R⁵ R⁶, --SO₂ NR R⁶ orphenyl; "het¹ ", used in the definition of R, means thienyl or a 5- or6-membered ring heteroaryl group containing either 1 or 2 nitrogenheteroatoms, or one nitrogen heteroatom and one oxygen or sulphurheteroatom, each optionally substituted by 1 or 2 substituents eachindependently selected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, fluoro(C₁-C₄)alkyl and fluoro(C₁ -C₄)alkoxy; "het² ", used in the definitions ofR³ and R⁴, means a 4- to 7-membered ring, non-aromatic, heterocyclicgroup containing 1 or 2 heteroatoms each independently selected fromnitrogen, oxygen and S(O)_(p), said group being optionally C-substitutedby 1 or 2 substituents each independently selected from C₁ -C₄ alkyl, C₁-C₄ alkoxy and fluoro(C₁ -C₄)alkyl, and said ring nitrogen heteroatomoptionally bearing a H, C₁ -C₄ alkyl, C₂ -C₅ alkanoyl, --CONR⁵ R⁶ or--SO₂ NR⁵ R⁶ substituent; and "het³ ", used in the definition of R²,means an optionally benzo-fused, N-linked, 5-membered ring heteroarylgroup containing from 1 to 4 nitrogen heteroatoms, optionallysubstituted, including in the benzo-fused portion, by 1 or 2substituents each independently selected from C₁ -C₄ alkyl, fluoro andfluoro(C₁ -C₄)alkyl.
 2. A compound as claimed in claim 1 whereinR is C₁-C₆ alkyl optionally substituted by --COOH, --COO(C₁ -C₄ alkyl), C₃ -C₇cycloalkyl, aryl or het¹, said cycloalkyl being optionally substitutedby 1 or 2 substituents each independently selected from C₁ -C₄ alkyl andfluoro; R¹ is phenyl optionally substituted by 1 or 2 halo substituents;R² is --CONR³ R⁴, --CONR⁵ (C₃ -C₇ cycloalkyl), --NR³ R⁴, het³ or a groupof the formula: ##STR513## where R³ and R⁴ are each independentlyselected from C₁ -C₄ alkyl and C₁ -C₄ alkyl substituted by hydroxy or C₁-C₄ alkoxy, R⁵ and R⁶ are each independently selected from H, C₁ -C₄alkyl optionally substituted by fluoro and C₃ -C₇ cycloalkyl-C₁ -C₄alkyl, R⁷ is H, hydroxy or phenyl, R⁸ is hydroxy or C₂ -C₅ alkanoyloxy,W is methylene, CH(OH), CH(C₁ -C₄ alkoxy), CHCO₂ H, CHCO₂ (C₁ -C₄alkyl), CH(benzoxazol-2-yl), CHNR⁵ R⁶, CHN R⁵ COR⁵, CHNR⁵ (SO₂ C₁ -C₄alkyl), CHNR⁵ COO(C₁ -C₄ alkyl), O, S(O)_(p), NR⁵, NSO₂ (C₁ -C₄ alkyl),NSO₂ NR⁵ R⁶, NSO₂ (morpholino), NCONR⁵ R⁶, NCOR⁵, NCO(aryl) or NCO₂ (C₁-C₄ alkyl), n is 1 or 2 when W is other than methylene and is 0 or 1when W is methylene, and p is 0,1 or 2; and X, X¹, X², m, aryl and het³are as previously defined in claim
 1. 3. A compound as claimed in claim2 whereinR is C₁ -C₆ alkyl optionally substituted by --COOH, --COO(C₁-C₄ alkyl), C₃ -C₇ cycloalkyl optionally substituted by 1 or 2substituents each independently selected from C₁ -C₄ alkyl and fluoro,phenyl optionally substituted by 1 or 2 substituents each independentlyselected from C₁ -C₄ alkyl, halo, C₁ -C₄ alkoxy, fluoro(C₁ -C₄)alkyl, C₂-C₅ alkanoyl, --SO₂ N(C₁ -C₄ alkyl)₂ and phenyl, or a 5- or 6-memberedring heteroaryl group containing 1 or 2 nitrogen heteroatoms; R¹ isphenyl optionally substituted by 1 or 2 substituents each independentlyselected from fluoro and chloro; R² is --CONR³ R⁴, --CONR⁵ (C₃ -C₇cycloalkyl), --NR³ R⁴, a N-linked, 5-membered ring heteroaryl groupcontaining 1 or 2 nitrogen heteroatoms, or a group of the formula:##STR514## where R³ and R⁴ are each independently selected from methyland C₁ -C₄ alkyl substituted by hydroxy or methoxy, R⁵ and R⁶ are eachindependently selected from H, methyl, trifluoromethyl andcyclopropylmethyl, R⁷ is H, hydroxy or phenyl, R⁸ is hydroxy oracetyloxy, W is methylene, CH(OH), CHOCH₃, CHOCH₂ CH₃, CHO(CH₂)₂ CH₃,CHOC(CH₃)₃, CHCO₂ H, CHCO₂ CH₃, CHCO₂ CH₂ CH₃, CH(benzoxazol-2-yl),CHNH₂, CHNHCH₂ (cyclopropyl), CH NHCOCH₃, CHNHSO₂ CH₃, CHNHCO₂ C(CH₃)₃,O, S(O)_(p), NH, NCH₃, NCH₂ (cyclopropyl), NSO₂ CH₃, NSO₂ NH₂, NSO₂NHCH₃, NSO₂ N(CH₃)₂, NSO₂ (morpholino), NCONH₂, NCONHCH₃, NCOCH₃,NCOCF₃, NCO(phenyl) or NCO₂ C(CH₃)₃, n is 1 or 2 when W is other thanmethylene and is 0 or 1 when W is methylene, and p is 0, 1 or 2; and X,X¹, X² and m are as previously defined in claim
 2. 4. A compound asclaimed in claim 3 whereinR is C₁ -C₆ alkyl optionally substituted by--COOH, --COO(C₁ -C₄ alkyl), C₃ -C₇ cycloalkyl optionally substituted by1 or 2 substituents each independently selected from methyl and fluoro,phenyl optionally substituted by 1 or 2 substituents each independentlyselected from methyl, fluoro, chloro, methoxy, trifluoromethyl, acetyl,--SO₂ N(CH₃)₂ and phenyl, or pyridinyl; and R¹, R², X, X¹, X² and m areas previously defined in claim
 3. 5. A compound as claimed in claim 4whereinR is 5-carboxypentyl, 5-tert-butyloxycarbonylpentyl,cyclopropylmethyl, dicyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, 2-methylcyclohexylmethyl,4,4-difluorocyclohexylmethyl, 2-cyclopropylethyl,2,2-dicyclopropylethyl, 1-cyclohexylethyl, 2-cyclohexylethyl,cycloheptyl-methyl, benzyl, 2-methylbenzyl, 3-methylbenzyl,4-methylbenzyl, 4-fluorobenzyl, 2,4-dichlorobenzyl, 3-methoxybenzyl,2-trifluoromethylbenzyl, 3,5-di(trifluoromethyl)benzyl, 3-acetylbenzyl,3-(N,N-dimethylsulphamoyl)-benzyl, 4-phenylbenzyl, 1-phenylethyl,2-pyridinylmethyl, 3-pyridinylmethyl or 4-pyridinylmethyl; R¹ is phenyl,3,4-difluorophenyl, 3-chlorophenyl, 4-chlorophenyl or3,4-dichlorophenyl; R² is N-(2-methoxyethyl)-N-methylcarbamoyl,N-cyclohexylcarbamoyl, N-(2-hydroxyethyl)-N-methylamino,N-(2-hydroxy-2-methylpropyl)-N-methylamino,N-(2-methoxyethyl)-N-methylamino, imidazol-1-yl,3-hydroxypyrrolidin-1-yl, piperidin-1-yl, 2,6-dimethylpiperidin-1-yl,3-hydroxypiperidin-1-yl, 4-hydroxypiperidin-1-yl,4-methoxypiperidin-1-yl, 4-ethoxypiperidin-1-yl,4-(n-propoxy)piperidin-1-yl, 4-(t-butoxy)piperidin-1-yl,4-carboxypiperidin-1-yl, 4-methoxycarbonylpiperidin-1-yl,4-ethoxycarbonylpiperidin-1-yl, 4-(benzoxazol-2-yl)piperidin-1-yl,4-aminopiperidin-1-yl, 4-cyclopropyl-methylaminopiperidin-1-yl,4-acetamidopiperidin-1-yl, 4-methane-sulphonamidopiperidin-1-yl,4-(t-butoxycarbonylamino)piperidin-1-yl, morpholino, 2-phenylmorpholino,homomorpholino, thiomorpholino, 1-oxothiomorpholino,1,1-dioxothiomorpholino, piperazin-1-yl, 4-methylpiperazin-1-yl,4-cyclopropylmethylpiperazin-1-yl, 4-methane-sulphonylpiperazin-1-yl,4-aminosulphonylpiperazin-1-yl, 4-methylamino-sulphonylpiperazin-1-yl,4-dimethylaminosulphonylpiperazin-1-yl,4-morpholinosulphonylpiperazin-1-yl, 4-carbamoylpiperazin-1-yl,4-N-methylcarbamoylpiperazin-1-yl, 4-acetylpiperazin-1-yl,4-trifluoroacetyl-piperazin-1-yl, 4-benzoylpiperazin-1-yl,4-(t-butoxycarbonyl)piperazin-1-yl, pyrrolidin-1-ylcarbonyl,piperidin-1-ylcarbonyl, 3-oxomorpholino,3-hydroxy-8-azabicyclo[3,2,1]oct-8-yl or3-acetyloxy-8-azabicyclo[3,2,1]oct-8-yl; X is ethylene or propylene; X¹is a direct link; X² is a direct link or CO; and m is as previouslydefined in claim
 4. 6. A compound as claimed in claim 5 whereinR iscyclopropylmethyl, dicyclopropylmethyl, 2-cyclopropylethyl,2,2-dicyclopropylethyl, cyclohexylmethyl, 4,4-difluorocyclohexylmethyl,cycloheptylmethyl or benzyl; R¹ is 3,4-difluorophenyl, 4-chlorophenyl or3,4-dichlorophenyl; R² is 4-aminopiperidin-1-yl,4-carboxypiperidin-1-yl, 4-hydroxypiperidin-1-yl, morpholino,1-oxothiomorpholino, 4-aminosulphonylpiperazin-1-yl,4-methanesulphonylpiperazin-1-yl, 4-methylaminosulphonylpiperazin-1-yl,4-morpholinosulphonylpiperazin-1-yl, 4-fluoropiperidin-1-yl,4,4-difluoropiperidin-1-yl, 4-oxopiperidin-1-yl,4-(pentafluorophenylsulphonyl)-piperazin-1-yl and4-(4-fluorophenylsulphonyl)piperazin-1-yl; X is ethylene; X² is a directlink; m is 1; and X¹ is as previously defined in claim
 5. 7. A compoundas claimed in claim 1 wherein X is --CH₂ CH₂ -- and which has the(S)-stereochemistry at the position of attachment of the X and R¹ groupsto the lactam ring.
 8. A compound as claimed in claim 1 wherein(i) R iscyclopropylmethyl, R¹ is 3,4-dichlorophenyl, R² is morpholino, X is--CH₂ CH₂ --, X¹ is a direct link and m is 1; (ii) R is4,4-difluorocyclohexylmethyl, R¹ is 3,4-dichlorophenyl, R² ismorpholino, X is --CH₂ CH₂ --, X¹ is a direct link and m is 1; (iii) Ris 4,4-difluorocyclohexylmethyl, R¹ is 3,4-dichlorophenyl, R² is4-aminopiperidin-1-yl, X is --CH₂ CH₂ --, X¹ is a direct link and m is1; (iv) R is cyclopropylmethyl, R¹ is 3,4-dichlorophenyl, R² is4-aminosulphonylpiperazin-1-yl, X is --CH₂ CH₂ --, X¹ is a direct linkand m is 1; (v) R is 4,4-difluorocyclohexylmethyl, R¹ is3,4-dichlorophenyl, R² is 4-hydroxypiperidin-1-yl, X is --CH₂ CH₂ --, X¹is a direct link and m is 1; (vi) R is 2-cyclopropylethyl, R¹ is3,4-dichlorophenyl, R² is morpholino, X is --CH₂ CH₂ --, X¹ is a directlink and m is 1; (vii) R is 2-cyclopropylethyl, R¹ is3,4-dichlorophenyl, R² is 4-methanesulphonylpiperazin-1-yl, X is --CH₂CH₂ --, X¹ is a direct link and m is 1; (viii) R is cyclopropylmethyl,R¹ is 3,4-dichlorophenyl, R² is 4-fluoropiperidin-1-yl, X is --CH₂ CH₂--, X¹ is a direct link and m is 1; (ix) R is4,4-difluorocyclohexylmethyl, R¹ is 3,4-dichlorophenyl, R² is4-oxopiperidin-1-yl, X is --CH₂ CH₂ --, X¹ is a direct link and m is 1;(x) R is cyclopropylmethyl, R¹ is 3,4-dichlorophenyl, R² is4-carboxypiperidin-1-yl, X is --CH₂ CH₂ --, X¹ is a direct link and m is1; or (xi) R is cyclohexylmethyl, R¹ is 3,4-dichlorophenyl, R² is4-carboxypiperidin-1-yl, X is --CH₂ CH₂ --, X¹ is a direct link and m is1:or any such compound with the (S)-stereochemistry at the position ofattachment of the X and R¹ groups to the lactam ring, or apharmaceutically acceptable salt of any thereof.
 9. A pharmaceuticalcomposition comprising a compound of the formula (I), or apharmaceutically acceptable salt thereof, as claimed in claim 1,together with a pharmaceutically acceptable diluent or carrier.
 10. Apharmaceutical composition for a disorder or condition that can betreated by producing an antagonist effect on a tachykinin acting at thehuman NK₁, NK₂, or Nk₃ receptor or a combination thereof, comprising anamount of a compound of claim 1, or a pharmaceutically acceptable saltthereof, that is effective in treating such disorder or condition.
 11. Amethod of treating a disorder or condition that can be treated byproducing an antagonist effect on a tachykinin acting at the human NK₁,NK₂, or Nk₃ receptor or a combination thereof, which comprisesadministering to said human an effective amount of a compound of claim1, or a pharmaceutically acceptable salt thereof.
 12. A compound asclaimed in claim 1 of the formula: ##STR515## or a pharmaceuticallyacceptable salt thereof, wherein R is C₁ -C₆ alkyl optionallysubstituted by fluoro, C₃ -C₇ cycloalkyl, adamantyl, aryl or het¹, saidcycloalkyl being optionally substituted by 1 or 2 substituents eachindependently selected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy, hydroxy,fluoro, fluoro(C₁ -C₄ alkyl) and fluoro(C₁ -C₄)alkoxy;R₁ is phenyloptionally substituted by 1 or 2 substituents each independentlyselected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo and trifluoromethyl, oris naphthyl or thienyl; R² is --CO₂ H, --CONR³ R⁴, --CONH(C₃ -C₇cycloalkyl), --CON(C₁ -C₄ alkyl)(C₃ -C₇ cyclbalkyl), --NH(C₂ -C₅alkanoyl), --N(C₁ -C₄ alkyl)(C₂ -C₅ alkanoyl), --NR³ R⁴ het³ or a groupof the formula: ##STR516## R³ and R⁴ are each independently selectedfrom H and C₁ -C₄ alkyl optionally substituted by hydroxy, C₁ -C₄alkoxy, --S(O)_(p) (C₁ -C₄ alkyl), amino, --NH(C₁ -C₄ alkyl), --N(C₁ -C₄alkyl)₂ or het² ; R⁵ and R⁶ are each independently selected from H andC₁ -C₄ alkyl; R⁷ is H, C₁ -C₄ alkyl, hydroxy, fluoro(C₁ -C₄)alkyl orphenyl optionally substituted by 1 or 2 substituents each independentlyselected from C₁ -C₄ alkyl, halo, C₁ -C₄ alkoxy and fluoro(C₁-C₄)alkoxy; R⁸ is H, fluoro, hydroxy, C₁ -C₄ alkoxy, C₂ -C₅ alkanoyl orC₂ -C₅ alkanoyloxy; X is C₁ -C₄ alkylene; W is methylene, CH(OH), CH(C₁-C₄ alkoxy), CHF, CF₂, CHNH(C₁ -C₄ alkyl), CHN(C₁ -C₄ alkyl)₂₁ CH(azetidin-1-yl), CH(pyrrolidin-1-yl), CH(piperidin-1-yl), CHNH(C₂ -C₅alkanoyl), CHN(C₁ -C₄ alkyl)(C₂ -C₅ alkanoyl), CHNHSO₂ (C₁ -C₄ alkyl),CHN(C₁ -C₄ alkyl)(SO₂ (C₁ -C₄ alkyl)), O, S(O)_(p), NH, N(C₁ -C₄ alkyl),NSO₂ (C₁ -C₄ alkyl), NSO₂ NH₂, NSO₂ NH(C₁ -C₄ alkyl), NSO₂ N(C₁ -C₄alkyl)₂, NCONH₂, NCONH(C₁ -C₄ alkyl), NOON(C₁ -C₄ alkyl)₂, N(C₂ -C₅alkanoyl) or NCO₂ (C₁ -C₄ alkyl); m is 0 or 1; n is 1 or 2 when W isother than methylene and is 0, 1 or 2 when W is methylene; p is 0, 1 or2; "aryl", used in the definition of R, means naphthyl or phenyl, bothoptionally substituted by 1 or 2 substituents each independentlyselected from C₁ -C₄ alkyl, halo, C₁ -C₄ alkoxy, fluoro(C₁ -C₄)alkyl,fluoro(C₁ -C₄)alkoxy, C₂ -C₅ alkanoyl, --CONH₂, --CONH(C₁ -C₄ alkyl),--CON(C₁ -C₄ alkyl)₂, --SO₂ NH₂, --SO₂ NH(C₁ -C₄ alkyl), --SO₂ N(C₁ -C₄alkyl)₂ and phenyl; "het¹ ", used in the definition of R, means a 5- or6-membered ring heteroaryl group containing either 1 or 2 nitrogenheteroatoms, or one nitrogen heteroatom and one oxygen or sulphurheteroatom; "het² ", used in the definitions of R³ and R⁴, means a 4- to7-membered ring, non-aromatic, heterocyclic group containing 1 or 2heteroatoms each independently selected from nitrogen, oxygen andS(O)_(p), said group being optionally C-substituted by 1 or 2substituents each independently selected from C₁ -C₄ alkyl, C₁ -C₄alkoxy and fluoro(C₁ -C₄)alkyl, and said ring nitrogen heteroatomoptionally bearing a H, C₁ -C₄ alkyl, C₂ -C₅ alkanoyl, --CONH₂,--CONH(C₁ -C₄ alkyl), --CON(C₁ -C₄ alkyl)₂, --SO₂ NH₂, --SO₂ NH(C₁ -C₄alkyl) or --SO₂ N(C₁ -C₄ alkyl)₂ substituent; and "het³ ", used in thedefinition of R², means a N-linked, 5-membered ring heteroaryl groupcontaining from 1 to 4 nitrogen heteroatoms and optionally substitutedby 1 or 2 substituents each independently selected from C₁ -C₄ alkyl andfluoro(C₁ -C₄)alkyl.